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Preoperative Chemoradiotherapy Using Taxanes for Locally Advanced Esophageal Carcinoma

Saint Luke’s HospitalRathgar, Dublin, Ireland
Association Europèenne de Récherche en OncologieHôpital Albert ChenevierAssistance Publique Hôpitaux de ParisParis, France

To the Editor:In their article, Adelstein et al¹ review a single-center 6-year experience in the treatment of patients with resectable, locally advanced esophageal carcinoma by combined-modality therapy. In view of the 23% overall pathologic complete tumor response rate (pCR) (8% for adenocarcinoma) obtained with a preoperative chemoradiotherapy combination of paclitaxel and cisplatin and its high toxicity, compared with the results previously obtained with a similar combination using fluorouracil and cisplatin (overall pCR 27%, 22% for adenocarcinoma), the authors conclude that these results no longer support the use of paclitaxel in their esophageal cancer neoadjuvant chemoradiotherapy program.

However, despite their conclusion, no difference in the oncologic outcomes is definitively demonstrated between the two treatment regimens. Even the dramatic comparison of the pCR for adenocarcinoma (22 of 45 v two of 25) is not statistically significant (Fisher’s exact test, P = .19). The authors report the other end points (tumor resectability, survival, and local and distant metastatic control rate) as similar in the two treatment groups. Thus, one cannot assume that there is a difference in the oncologic outcome between the two regimens, even irrespective of the nonrandomized design of the comparison. Moreover, the relevance of the comparison of the two treatment groups is questionable. Multiple methodologic questions remain unanswered: the prospective design of the nonrandomized comparison, the sample size calculation, stopping rules, and judgment criteria are to be questioned. Because of the extent of the accrual period of the two studies (1991 to 1997), tumor staging methods and resectability criteria should also be precisely reported to allow comparison. Also of concern is the fact that both studies have previously been reported,^2-8 without evidence of major problems in the short-term end points (pCR, toxicity) for the paclitaxel arm.

To our knowledge, three other phase II trials of a quite similar preoperative combination of paclitaxel, cisplatin, and radiotherapy have been reported ( Table 1).^9-11 Considering the reported phase II, one can only conclude that the combination of paclitaxel, cisplatin, and radiotherapy can lead to a pCR of 12% to 22% in patients with resectable, locally advanced esophageal carcinoma. When these last results are put into perspective with the results of numerous phase II and III trials of fluorouracil, cisplatin, and radiotherapy showing pCRs of 17% to 29%, no formal conclusion can be drawn. Only a comparison of the two treatment regimens through a randomized phase III trial would be conclusive.

Among them, the timing of administration of paclitaxel and irradiation was shown to be crucial, with a maximum therapeutic ratio (increased tumor radiosensitivity and critical organ protection) occurring from 6 to 24 hours to 72 hours after exposure to the drug.¹² It should be noted that the combination used led to delivery of about half of the radiation dose outside this period. Moreover, the radiotherapy scheme used in the Cleveland Clinic Foundation trial cannot be considered as an accelerated scheme (shortest overall treatment time) because the preoperative radiation dose of 45 Gy was delivered over an overall treatment time of 4.5 weeks (equivalent to the 10 Gy/week of a conventional radiotherapy scheme); rather it is a hyperfractionated split-course scheme (with a midtreatment interruption). In radical radiotherapy for esophageal carcinoma, increased overall treatment time and midtreatment interruption have a negative impact on treatment efficacy mainly because of the tumor repopulation they allow.¹³ It should be pointed out that the only positive randomized trials¹⁴ of preoperative chemoradiation combination, among the six published, was the only one that proposed a hyperfractionated continuous irradiation scheme (45 Gy over 19 days).

The conclusion that "paclitaxel-based treatments must be carefully and prospectively studied before their incorporation into the standard management of esophageal cancer" that appears in the abstract is unfortunately not developed in the article, but seems to us more accurate. The title of the article is misleading, as such a study cannot answer whether or not a specific product improves a treatment modality. The combined preoperative treatment of esophageal carcinoma may not need paclitaxel, but the evidence reported by Adelstein et al¹ is insufficient to make this conclusion. At least five studies (phase I, phase II, and phase I/II trials) are currently underway to find the optimal schedule for the incorporation of taxanes, including paclitaxel, taking into account the complexity of their interaction with radiation.

REFERENCES

1. Adelstein DJ, Rice TW, Rybicki LA, et al: Does paclitaxel improve the chemoradiotherapy of locoregionally advanced esophageal cancer? A nonrandomized comparison with fluorouracil-based therapy. J Clin Oncol 18: 2032-2039, 2000[Abstract/Free Full Text]

2. Adelstein DJ, Rice TW, Tefft M, et al: Neoadjuvant chemotherapy (CT) and concurrent hyperfractionated radiation (HRT) for esophageal cancer. Proc Am Soc Clin Oncol 14: 191, 1995 (abstr 442)

3. Adelstein DJ, Rice TW, Becker M, et al: Concurrent chemotherapy (CCT), accelerated fraction radiation (AFR) and surgery for patients with esophageal cancer. Proc Am Soc Clin Oncol 15: 203, 1996 (abstr 454)

4. Adelstein DJ, Rice TW, Becker M, et al: Use of concurrent chemotherapy, accelerated fractionation radiation, and surgery for patients with esophageal cancer. Cancer 80: 1011-1020, 1997[Medline]

5. Adelstein DJ, Rice TW, Rybicki LA, et al: Concurrent chemoradiotherapy and surgery for esophageal cancer: Updated results. Can J Gastroenterol 12: 15B, 1998 (suppl B, abstr 26)

6. Adelstein DJ, Rice TW, Becker M, et al: Accelerated fractional radiation (AFR), concurrent cisplatin (DDP)/paclitaxel (TAX) chemotherapy (CT) and surgery for locoregionally advanced esophageal cancer. Proc Am Soc Clin Oncol 16: 160a, 1997 (abstr 924)

7. Adelstein DJ, Rice TW, Rybicki LA, et al: Concurrent cisplatin (DDP)/paclitaxel (TAX) chemotherapy, accelerated fractionation radiation (AFR) and surgery for esophageal cancer: Updated results. Can J Gastroenterol 12: 16b, 1998 (suppl B, abstr 27)

8. Chidel MA, Rice TW, Adelstein DJ, et al: Resectable esophageal carcinoma: Local control with neoadjuvant chemotherapy and radiation therapy. Radiology 213: 67-72, 1999[Abstract/Free Full Text]

9. Safran H, Gaissert H, Hesketh PJ, et al: Neoadjuvant paclitaxel, cisplatin and radiation for esophageal carcinoma: A phase II study. Proc Am Soc Clin Oncol 16: 304a, 1997 (abstr 1081)

10. Blanke C, Chiappori A, Epstein B, et al: A phase II trial of neoadjuvant paclitaxel (T) and cisplatin (P) with radiotherapy followed by surgery (S) and postoperative T with 5-fluorouracil (F) and leucovorin (L) in patients (pts) with locally advanced esophageal cancer (LAEC). Proc Am Soc Clin Oncol 16: 283a, 1997 (abstr 1006)

11. Urba S, Orringer M, Iannettoni M, et al: A phase II trial of preoperative cisplatin, paclitaxel, and radiation therapy (XRT) before trans-hiatal esophagectomy (THE) in patients (Pts) with loco-regional esophageal cancer (CA). Proc Am Soc Clin Oncol 19: 248a, 2000 (abstr 960)

12. Milas L, Milas MM, Mason KA: Combination of taxanes with radiation: Preclinical studies. Semin Radiat Oncol 9: 12-26, 1999[Medline]

13. Nishimura Y, Ono K, Tsutsui K, et al: Esophageal cancer treated with radiotherapy: Impact of total treatment time and fractionation. Int J Radiat Oncol Biol Phys 30: 1099-1105, 1994[Medline]

14. Walsh TN, Noonan N, Hollywood D, et al: A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 335: 462-467, 1996[Abstract/Free Full Text]

Response

Cleveland Clinic FoundationCleveland, OH

In Reply:Drs Thirion and Piedbois have restated and reinforced our conclusions regarding the use of paclitaxel in the chemoradiotherapy of esophageal cancer.¹ We agree completely with their assessment. As carefully noted several times in our article, the comparison made between the fluorouracil (5-FU) regimen and the paclitaxel regimen is nonrandomized and retrospective. These were two consecutively treated patient groups, and the limitations of this comparison were stressed. Our conclusion in the abstract and in the article is the same. A careful prospective investigation of paclitaxel-containing regimens is mandatory before the incorporation of paclitaxel into the standard management of esophageal cancer. The 5-FU and cisplatin combination has been well studied and represents the standard of care at the present time. The taxanes are interesting and active agents, but their use in this disease requires careful evaluation. As pointed out by Thirion and Piedbois, a number of phase I and II studies (including our own) have been reported or are underway, and better ways to administer this drug certainly exist. Only phase III randomized trials, however, will settle this issue.

The purpose of a phase II trial is to both define the feasibility of a treatment regimen and identify whether a regimen is sufficiently promising that further study is warranted. The purpose of our article was to raise the question of whether the use of paclitaxel improves the current standard of care. Clearly we were unable to answer this question in a nonrandomized, retrospective fashion. Although the paclitaxel-containing protocol proved feasible (albeit toxic), the results were not sufficiently promising, nor were they dramatically better than those obtained with 5-FU and cisplatin. As such, we are not investigating paclitaxel further in this disease at our institution. This should not be interpreted as a recommendation to discontinue all further study of this agent. It is, however, an acknowledgement of the fact that the drug is not ready for prime-time in this disease and should not be considered part of standard chemoradiotherapy regimens.

REFERENCES

1. Adelstein DJ, Rice TW, Rybicki LA, et al: Does paclitaxel improve the chemoradiotherapy of locoregionally advanced esophageal cancer? A nonrandomized comparison with fluorouracil-based therapy. J Clin Oncol 18: 2032-2039, 2000

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This Article 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 Thirion, P. Articles by Adelstein, D. J. Search for Related Content PubMed PubMed Citation Articles by Thirion, P. Articles by Adelstein, D. J. Social Bookmarking                            What's this?