Originally published as JCO Early Release 10.1200/JCO.2005.02.904 on June 6 2005

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 HighWire Citing Articles via Google Scholar Google Scholar Articles by Turrisi, A. T. Search for Related Content PubMed PubMed Citation Articles by Turrisi, A. T., III Related Articles Related Article Social Bookmarking                            What's this?

Creeping Phase II-ism and the Medical Pharmaceutical Complex: Weapons of Mass Distraction in the War Against Lung Cancer

Wayne State University School of Medicine; Barbara Ann Karmanos Cancer Institute; and the Detroit Medical Center, Gershenson Radiation Oncology Center, Detroit, MI

This issue reports the long-awaited Radiation Therapy Oncology Group (RTOG) phase II study¹ that incorporated paclitaxel, the new drug of the 1990s, with standard twice-daily radiotherapy and cisplatin plus etoposide, which was presented initially at the 36th Annual Meeting of the American Society of Clinical Oncology (ASCO) in 2000.² In that abstract, the authors addressed the following questions. Can the addition of paclitaxel to etoposide and cisplatin result in improved survival for patients with limited small-cell lung cancer (SCLC)? Can the addition of paclitaxel improve on the results (1-year survival of 70% and median survival of 23 months) of the best arm of the Intergroup study?^2,3 They reported that the 1-year survival rate on their study was 83%, inferring an advantage at this unorthodox benchmark, but the median survival had not yet been reached. Ettinger et al¹ have more carefully modified their prose in preparing this final report for the trial and parsed every phrase to diligently inform all and offend no one. At the end of the day, the addition of paclitaxel to etoposide plus cisplatin provides no advantage to standard treatment without paclitaxel, which is similar to the conclusion of the results of the extensive disease trial that incorporated these three drugs.⁴ Moreover, as in most lung cancer trials, the third drug adds toxicity without survival benefit.

Unlike this sober and direct final report and the abstract on the phase III study in extensive-disease SCLC,⁴ the original abstract and preliminary presentation of these data perhaps over-optimistically forecast the survival benefit for this three-drug combination administered with concurrent twice-daily radiotherapy. We are all enthusiastic about our work and interested that the world should know about its promise. But, is it really useful news that the abstract proffered information that was ultimately misleading about the final outcome and importance of the study? This was a phase II cooperative group trial initially reported as a preliminary result. Although it may not be news, there are unintended consequences of the practice of magnifying the importance of such preliminary results at the Annual Meetings of ASCO and creating too much enthusiasm for phase II study results. A San Francisco newspaper expressed concern to ASCO that the data presented at these meetings and in the abstract book might "move the market" and represent "insider trading" (perhaps a concern for an entirely different editorial in the future). I am more concerned that such reports move the hearts and minds of the clinical practice community, perhaps too soon for these preliminary results. At the same time, such preliminary reports also throw clinical research into a state of uncertainty. Determining what is truly promising from what is hyperbole can be quite difficult with too early results. Sometimes, we as authors stretch to find a measure that makes results seem better or more important than they are. We have to be particularly cautious about phase II results, preliminary or otherwise, and downright dubious about fanciful claims and novel end points, such as 1-year survival, in lung cancer or any other disease.

Paclitaxel promised great hope in lung cancer, but now that results of mature trials are available, it has produced some frankly disappointing results compared with our initial expectations. It is clearly not as good as the lung cancer pundits forecasted or preached at advisory boards. Obviously, paclitaxel has some activity, but despite a different mechanism of action and toxicity profile from cisplatin and etoposide, it does not seem to add significant benefit to those drugs in SCLC. Similarly, there is a real issue as to whether it is better, the same, or not as good in locally advanced⁴ or metastatic non–small-cell lung cancer (NSCLC).⁵ A final report at the ASCO Annual Meeting in 1998 of a randomized phase III study of paclitaxel has not, as yet, seen publication in a peer-reviewed journal.⁶ Are paclitaxel combinations really better than cisplatin plus etoposide for SCLC or NSCLC? I can ask this about paclitaxel more confidently today, but paclitaxel combination enthusiasm was surging in 2000 when the initial RTOG abstract reported its superiority in 1-year survival compared with a similar point on the curve of the Intergroup trial and suggested that this was going to be a meaningful advance. Is 1-year survival really a useful or meaningful end point for limited SCLC research? Although it turned out not to be a meaningful end point, it did freeze the frames of mind for many and bolstered arguments about where to invest limited resources of SCLC patients for the conduct of clinical trials. Furthermore, this end point also highlights that preliminary results bear false witness when they are compared with the results of published, mature phase III trials. What is realistic to expect from phase II data in limited-disease SCLC, and when can we be optimistic that there is a result that raises something other than false hope? Do we need to wait for study completion and follow-up for 3 to 4 years before we can pay attention to what seems like an advance? RTOG 9609 must have been conceived before 1996, and preliminary results were presented in 2000, but we only have the facts now more than 8 years since the study was designed.

The 2000 abstract² of the study finally reported in this issue hinted that a phase III trial was being prepared, but the article¹ forecasts the latest RTOG idea about fractionation with a dose of 61.2 Gy in 5 weeks and 9 days of twice-daily 1.8-Gy treatment.⁷ This delivers the accelerated treatment in 5 weeks, but it overlaps with two cycles of chemotherapy and remains limited by esophagitis. We also have no clue about whether the radiation oncology community will accept 9 days of twice-daily treatment more readily than 15 days. When and how will we know if this fractionation scheme is an advance compared with 3 weeks of 1.5 Gy to a total dose of 45 Gy, which is the apparent standard schedule with the best-reported 5-year survival rate of 26%?³ Since completion of the North Central Cancer Treatment Group Study in 1996,⁸ there have been no active national phase III trials in limited SCLC. Since the publication of the Intergroup trial in 1999,³ no report has matched the survival with the accelerated twice-daily regimen, but few follow the evidence, preferring a once-daily method despite a lack of evidence. Although trials have been proposed, preliminary results and fractionation misconceptions have been substituted for a phase III trial with a radiotherapy dose question.

Even today in lung cancer clinical trials, phase II results disturbingly are preliminarily presented with incredible and unreproduced results. Three examples of "creeping phase II-ism" involve docetaxel. Southwest Oncology Group trial 0023 leans heavily on the results of its pilot study, which showed that three adjuvant cycles of docetaxel seemed to produce better results in stage IIIb NSCLC⁹ compared with an earlier trial that did not have the adjuvant therapy. A Swiss phase II study used docetaxel and cisplatin before surgery in stage IIIa NSCLC¹⁰ and reported a high frequency of pathologic clearance of N2 nodes. A large Intergroup trial¹¹ that tested the benefit of surgery in stage IIIa NSCLC after induction chemoradiotherapy, despite abstracts with apparently conflicting results,¹² does not seem to demonstrate a clear benefit to surgery. Notwithstanding those results, coupled with the optimistic Swiss report, the next Intergroup stage IIIa NSCLC trial ignores the larger negative phase III results in favor of the optimistic results from the unconfirmed phase II study from Switzerland. Therefore, phase II studies sometimes have inordinate influence, especially when they demonstrate results that we want to see. I am still puzzled about why strong evidence is commonly ignored, especially when it does not "move the market" or have an economic incentive. Although I have faith in my colleagues, I wonder if the marketing has more influence than data, or perhaps, it is the prospect of hopefulness that moves clinical oncologists.

We seek to do what is best for our patients, and such practice at times is difficult to define, despite ASCO and National Comprehensive Cancer Network guidelines. We know that current therapies in lung cancer leave a lot to be desired, but the desire that a new drug, targeted or otherwise, will alter the current situation seems to result in more hope than common sense and recent data would suggest. Although the fame and fortune aspect does dance like sugarplums in investigators' and clinicians' heads, the infamy of false promises and misleading spin-doctoring of phase II trials and the potential misfortune of the consequences seem to be worth thinking about.

Author's Disclosures of Potential Conflicts of Interest

The following author or their immediate family members has indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Andrew T. Turrisi III Aventis (A); AstraZeneca (A); Bristol-Myers (A); Medimmune (A) Gaca; Rovner, Crenny

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

REFERENCES

1. Ettinger DS, Berkey BA, Abrams RA, et al: Study of paclitaxel, etoposide, and cisplatin chemotherapy combined with twice-daily thoracic radiotherapy for patients with limited-stage small-cell lung cancer: A Radiation Therapy Oncology Group 9609 phase II study. J Clin Oncol 23:4991-4998, 2005

2. Ettinger DS, Seiferheld WF, Abrams RA, et al: Cisplatin (P), etoposide (E), paclitaxel (T) and concurrent hyperfractionated thoracic radiotherapy (TRT) for patients (pts) with limited disease (LD) small cell lung cancer (SCLC): Preliminary results of RTOG 96-09. Proc Am Soc Clin Oncol 19:490a, 2000 (abstr 1917)

3. Turrisi AT, Kim K, Blum R, et al: Twice daily compared with once-daily thoracic radiotherapy in limited small cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 340: 265-271, 1999[Abstract/Free Full Text]

4. Neill HB, Herndon JE, Miller AD, et al: Randomized phase III trial (CALGB 9732) of etoposide and cisplatin with or without paclitaxel and G-CSF in patients with extensive stage small cell lung cancer. Proc Am Soc Clin Oncol 21: 293a, 2002 (abstr 1169)

5. Vokes EE, Herndon JE, Kelley MJ, et al: Induction chemotherapy followed by concomitant chemoradiotherapy (CT/XRT) versus CT/XRT alone for regionally advanced unresectable non-small cell lung cancer (NSCLC): Initial analysis of a randomized phase III trial. J Clin Oncol 22:616, 2004 (suppl, abstr 7005)

6. Belani CP, Natale RB, Lee JS, et al: Randomized phase III trial comparing cisplatin etoposide versus carboplatin/paclitaxel in advanced and metastatic non-small cell lung cancer (NSCL). Proc Am Soc Clin Oncol 17:455a, 1998 (abstr 1751)

7. Komaki R, Swann S, Ettinger D, et al: Phase I dose escalation study of thoracic irradiation with concurrent chemotherapy for patients with limited small cell lung cancer (LSCLC): Radiation Therapy Oncology Group (RTOG). Int J Radiat Oncol Biol Phys 57:S139, 2003 (suppl 2, abstr 25)

8. Schild SE, Bonner JA, Shanahan TG, et al: Long-term results of a phase III trial comparing once-daily radiotherapy with twice-daily radiotherapy in limited-stage small cell lung cancer. Int J Radiat Oncol Biol Phys 59: 943-951, 2005[CrossRef]

9. Gandara DR, Chansky K, Albain KS, et al: Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIb non–small-cell lung cancer: Phase II Southwest Oncology Group study S9504. J Clin Oncol 21: 2004-2010, 2003[Abstract/Free Full Text]

10. Betticher DC, Schmitz SFH, Tötsch M, et al: Mediastinal lymph node clearance after docetaxel-cisplatin neoadjuvant chemotherapy is prognostic of survival in patients with stage IIIA non–small-cell lung cancer: A multicenter phase II trial. J Clin Oncol 21: 1752-1759, 2003[Abstract/Free Full Text]

11. Albain KS, Scott CB, Rusch VR, et al: Phase III comparison of concurrent chemotherapy plus radiotherapy (CT/RT) and CT/RT followed by surgical resection for stage IIIa (pN-2) non-small-cell lung cancer (NSCLC): Initial results from intergroup trial 0139 (RTOG 9309). Proc Am Soc Clin Oncol 22:621, 2003 (abstr 2497)

12. Turrisi AT, Scott CB, Rusch VR, et al: Randomized trial of chemoradiotherapy to 61 Gy [no S] versus chemoradiotherapy to 45 Gy followed by surgery [S] using cisplatin etoposide in stage IIIa non-small-cell lung cancer (NSCLC): Intergroup trial 0139, RTOG 9309. Int J Radiat Oncol Biol Phys 57:S125, 2003 (suppl 2, abstr 4)

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Related Article

• Study of Paclitaxel, Etoposide, and Cisplatin Chemotherapy Combined With Twice-Daily Thoracic Radiotherapy for Patients With Limited-Stage Small-Cell Lung Cancer: A Radiation Therapy Oncology Group 9609 Phase II Study
  David S. Ettinger, Brian A. Berkey, Ross A. Abrams, James Fontanesi, Mitchell Machtay, Philip J. Duncan, Walter J. Curran, Jr, Benjamin Movsas, and Roger W. Byhardt
  JCO 2005 23: 4991-4998 [Abstract] [Full Text]

This article has been cited by other articles:

				R. P. Abratt, W. H.H. Reece, N. H. Enas, and R. Stephens Randomized phase II studies and their ethics. J. Clin. Oncol., December 20, 2005; 23(36): 9443 - 9443. [Full Text] [PDF]

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 HighWire Citing Articles via Google Scholar Google Scholar Articles by Turrisi, A. T. Search for Related Content PubMed PubMed Citation Articles by Turrisi, A. T., III Related Articles Related Article Social Bookmarking                            What's this?