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Targeting Pelvic Lymph Nodes in Men With Intermediate- and High-Risk Prostate Cancer, and Confusion About the Results of the Randomized Trials

Department of Radiation Oncology, University of California, San Francisco Cancer Center at Mount Zion, San Francisco, CA

To the Editor:

In a recent letter, Drs Nguyen and D'Amico¹ shared their opinions about what they believe should constitute the standard of care as it relates to the use of whole pelvic radiotherapy (WPRT). Unfortunately, I believe their conclusions were based on misinterpretations and faulty assumptions about Radiation Therapy Oncology Group (RTOG) 94-13, and ignore a growing body of the literature concerning the true incidence of lymph node involvement in patients with prostate cancer. Space does not permit me to address all of the issues in as much detail, so I will touch on a few of these points.

Nguyen and D'Amico misinterpret the update of RTOG 94-13, assuming it is negative, stating, "...with longer follow-up, there was no difference in progression-free survival." The fact is, the primary end point as defined by the study was progression-free survival (PFS), and this end point was reached as originally reported in 2003.² We set this end point at 5 years because we understood that early-on prostate-specific antigen failure would drive our assessment of outcomes. To avoid bias, we included death as a result of any cause as part of the PFS end point. With longer follow-up, death as a result of other causes became so common that the original definition became less clinically relevant for assessing the impact of WPRT.³ However, once a primary end point is reached at the predetermined time, it is reached. Furthermore, as shown in Lawton et al's Figures 3b and 5b,³ PFS and biochemical failure both continue to favor the WPRT arm (P = .034 and .0098, respectively), using the Phoenix definition. This definition has been shown to have a higher sensitivity and specificity for clinical failure and death, and is now the standard recommended for patients receiving androgen-deprivation therapy (ADT).⁴ We now await the major secondary end points, cause-specific and overall survival. At the time of the update, not enough events had occurred to determine whether WPRT is associated with an improvement in either of these end points. Of note however, the trends favors WPRT over the other three arms (prostate-only radiation therapy [PORT] + WPRT with adjuvant ADT, and PORT with neoadjuvant ADT), with cause-specific survivals approximately 90%, 85%, 80%, and 80%, respectively, at 10 years.³

Nguyen and D'Amico assume that RTOG 94-13 suggests "that pelvic radiation improved the primary end point of progression-free survival ... ."¹ This is not so: RTOG 9413 demonstrated that when WPRT was preceded by neoadjuvant ADT, it improved PFS in patients with a risk of lymph node involvement more than 15% using my equation. In fact, RTOG 9413 suggests that there is no advantage to WPRT over PORT without neoadjuvant ADT.

Nguyen and D'Amico wrote, "...the authors believe that an unexpected interaction has obscured the underlying benefit of a pelvic field, although no formal test for interaction was reported."¹ This is incorrect: we published the data demonstrating the interactions in our original report in 2003 on pages 1906 and 1907.² I recommend they reread the article.

Nguyen and D'Amico conclude that the findings of RTOG 94-13 are consistent with those from the Genito-Urinary Group–01 trial, writing that it "...provides validation of RTOG 94-13".⁵ This statement is incorrect. Only 205 of their 446 patients would have been eligible for RTOG 9413, and we do not know how many of them received neoadjuvant ADT because it was not required. Furthermore, none of the patients treated on their trial received WPRT as defined on RTOG 94-13. Their superior border was placed at S1-S2 interspace, and we have shown that smaller fields are less effective than larger fields.⁶ Thus, their findings neither shed light on, support, nor contradict RTOG 94-13.

Nguyen and D'Amico believe, based on the Partin nomograms and Surveillance, Epidemiology, and End Results staging system data, that "...today's patients are much less likely to have nodal involvement for a given [prostate-specific antigen] and Gleason score," and provide a table to make this point. There is a growing body of literature that suggests that surgical staging data based on a standard lymph node dissection (eg, Partin's data) substantially underestimates the true incidence of lymph node involvement.^7-10 These data series also are likely to underestimate the true incidence because the presacral nodes were not always included, and microscopic evaluation, long considered the gold standard, may miss 13% to 30% of occult involvement compared with more sensitive assays for involvement.^11-14 Thus, their assumptions are based on inaccurate data.

Nguyen and D'Amico conclude, "We believe that the use of the pelvic field should be restricted to men on studies... ." By this conclusion, the authors assume that the burden of proof should rest on those who choose to use WPRT to prove its value. This is based on their incorrect assumption that RTOG 9413 is a negative study, and ignores the fact that every major randomized trial demonstrating a survival advantage included WPRT. I would argue that, given the encouraging results of RTOG 94-13 and the fact that every major randomized trial demonstrating a survival in patients with high-risk disease included WPRT, the burden of proof should rest on those who choose not to use WPRT to prove it is equally effective.

Drs Nguyen and D'Amico should be commended for freely sharing their views. I am convinced that their assumptions and conclusions about WPRT happen to be wrong, but only time and more studies will answer this question.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Nguyen PL, D'Amico AV: Targeting pelvic lymph nodes in men with intermediate- and high-risk prostate cancer despite two negative randomized trials. J Clin Oncol 26:2055-2056, 2008; discussion 2056-2057[Free Full Text]

2. Roach M III, DeSilvio M, Lawton C, et al: Phase III trial comparing whole-pelvic versus prostate-only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413. J Clin Oncol 21:1904-1911, 2003[Abstract/Free Full Text]

3. Lawton CA, DeSilvio M, Roach M III, et al: An update of the phase III trial comparing whole pelvic to prostate only radiotherapy and neoadjuvant to adjuvant total androgen suppression: Updated analysis of RTOG 94-13, with emphasis on unexpected hormone/radiation interactions. Int J Radiat Oncol Biol Phys 69:646-655, 2007[Medline]

4. Roach M III, Hanks G, Thames H Jr, et al: Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: Recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys 65:965-974, 2006[CrossRef][Medline]

5. Pommier P, Chabaud S, Lagrange JL, et al: Is there a role for pelvic irradiation in localized prostate adenocarcinoma? Preliminary results of GETUG-01. J Clin Oncol 25:5366-5373, 2007[Abstract/Free Full Text]

6. Roach M III, DeSilvio M, Valicenti R, et al: Whole-pelvis, "mini-pelvis," or prostate-only external beam radiotherapy after neoadjuvant and concurrent hormonal therapy in patients treated in the Radiation Therapy Oncology Group 9413 trial. Int J Radiat Oncol Biol Phys 66:647-653, 2006[Medline]

7. Heidenreich A, Varga Z, Von Knobloch R: Extended pelvic lymphadenectomy in patients undergoing radical prostatectomy: High incidence of lymph node metastasis. J Urol 167:1681-1686, 2002[CrossRef][Medline]

8. Briganti A, Chun FK, Salonia A, et al: Critical assessment of ideal nodal yield at pelvic lymphadenectomy to accurately diagnose prostate cancer nodal metastasis in patients undergoing radical retropubic prostatectomy. Urology 69:147-151, 2007[CrossRef][Medline]

9. Briganti A, Chun FK, Salonia A, et al: A nomogram for staging of exclusive nonobturator lymph node metastases in men with localized prostate cancer. Eur Urol 51:112-119, 2007; discussion 119-120[CrossRef][Medline]

10. Briganti A, Chun FK, Salonia A, et al: Validation of a nomogram predicting the probability of lymph node invasion among patients undergoing radical prostatectomy and an extended pelvic lymphadenectomy. Eur Urol 49:1019-1026, 2006; discussion 1026-1027[CrossRef][Medline]

11. Shariat SF, Kattan MW, Erdamar S, et al: Detection of clinically significant, occult prostate cancer metastases in lymph nodes using a splice variant-specific rt-PCR assay for human glandular kallikrein. J Clin Oncol 21:1223-1231, 2003[Abstract/Free Full Text]

12. Pagliarulo V, Hawes D, Brands FH, et al: Detection of occult lymph node metastases in locally advanced node-negative prostate cancer. J Clin Oncol 24:2735-2742, 2006[Abstract/Free Full Text]

13. Ferrari AC, Stone NN, Kurek R, et al: Molecular load of pathologically occult metastases in pelvic lymph nodes is an independent prognostic marker of biochemical failure after localized prostate cancer treatment. J Clin Oncol 24:3081-3088, 2006[Abstract/Free Full Text]

14. Miyake H, Hara I, Kurahashi T, et al: Quantitative detection of micrometastases in pelvic lymph nodes in patients with clinically localized prostate cancer by real-time reverse transcriptase-PCR. Clin Cancer Res 13:1192-1197, 2007[Abstract/Free Full Text]

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Roach, M. Search for Related Content PubMed PubMed Citation Articles by Roach, M., III Social Bookmarking                            What's this?