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Evaluating Neoadjuvant Chemotherapy in Breast Cancer

Faxton-St Luke’s Healthcare, The Regional Cancer Center Radiation Oncology, Utica, NY

To the Editor:We read with interest the results of the European Organization for Research and Treatment of Cancer (EORTC) trial 10902 comparing neoadjuvant to adjuvant chemotherapy in operable breast cancer.¹ This trial, as in other similar trials, reports no improvement in progression-free and overall survival and locoregional tumor control. Sadly these trials report a 5% to 6% annual distant failure rate.

Unfortunately, many of these studies have compared two inadequate therapeutic approaches. In EORTC 10902, all patients had axillary node dissection (AND). Infra- and supraclavicular radiation was used in very selected patients. However, approximately 85% of patients had greater than T2 tumors, and approximately 5% had T4b tumors.

In patients with nonpalpable nodes, there is a 52% and 71% risk of pathologic involved nodes (pN+) in clinical T2 and T3 NoMo tumors, respectively.² These patients would best be treated with neoadjuvant or adjuvant chemotherapy, breast conservation surgery or mastectomy, and locoregional radiation, without AND. Radiation treats the entire chain of axillary (levels I, II, III), interpectoral (Rotter’s), and infra- and supraclavicular nodes. When indicated, internal mammary nodes can be included in the radiation field. AND deters nodal radiation,¹ and after neoadjuvant chemotherapy, looses its value as a staging tool. Response of the primary tumor to neoadjuvant chemotherapy could provide information on the chemosensitivity of the tumor.

Nodal radiation at the time of breast reduction achieves identical nodal control rates and eliminates the need for AND without increasing the cost of radiation therapy. There is increasing data from several randomized trials and meta-analyses that nodal radiation improves locoregional tumor control, and disease-free and overall survival with a reduction of cancer mortality.^3-5

AND deters radiation therapy to the nodes because of increased risk of breast and arm lymphedema. However, AND is indicated and therapeutic for palpable nodal disease. Then patients with extranodal spread or greater than three pN+ nodes need radiation to the axillary-infra-supraclavicular chain of nodes. Nodal status after neoadjuvant chemotherapy is futile and is a credit to the chemotherapy. However, to compromise radiation after neoadjuvant chemotherapy is disconcerting.⁶

Use of neoadjuvant chemotherapy refutes the argument that nodal information is needed for randomization and to select drug combination in invasive breast cancer. In fact, these patients would be better served with therapy to all the draining nodes rather than a diagnostic test on some nodes; later on, this test deters adequate nodal treatment. With identical axillary control rates for subclinical disease, replacing AND with nodal radiation saves patients from surgery, which has significant cost and morbidity. Without AND, breast surgery can be performed without patient admission, significant rehabilitation, and convalescence. We need to reconsider the policy that all invasive breast cancers need identical loco-regional treatment. Neo-adjuvant and/or adjuvant chemotherapy cannot compensate for inadequate loco-regional treatment.

REFERENCES

1. Van der Hage JA, Van de Velde CJH, Julien JP, et al: Preoperative chemotherapy in primary operable breast cancer: Results from the European Organization for Research and Treatment of Cancer Trial 10902. J Clin Oncol 19: 4224-4237, 2001[Abstract/Free Full Text]

2. McMasters K, Tuttle TM, Carlson DJ, et al: Sentinel lymph node biopsy for breast cancer: A suitable alternative to routine axillary dissection in multi-institutional practice when optimal technique is used. J Clin Oncol 18: 2560-2566, 2000[Abstract/Free Full Text]

3. Whelan TJ, Julian J, Wright J, et al: Does loco-regional radiation therapy improve survival in breast cancer? A meta-analysis. J Clin Oncol 18: 1220-1229, 2000[Abstract/Free Full Text]

4. Lawrence GA, Castro P, Collins B: Breast cancer: Systematic benefits of loco-regional treatment. J Clin Oncol 14: 1403-1404, 1996[Free Full Text]

5. Cuzick J, Stewart H, Rutqvist L, et al: Cause-specific mortality in long-term survivors of breast cancer that participated in trials of radiotherapy. J Clin Oncol 12: 447-453, 1994[Abstract]

6. Buchholz TA, Tucker SL, Masullo L, et al: Predictors of local-regional recurrence after neoadjuvant chemotherapy and mastectomy without radiation. J Clin Oncol 20: 17-23, 2001[Abstract/Free Full Text]

Response

Leiden University Medical Center, Leiden, the Netherlands

In Reply:We appreciate the comments of Lawrence, Crawford, and Sherman to our manuscript on preoperative versus postoperative chemotherapy in primary operable breast cancer (European Organization for Research and Treatment of Cancer [EORTC] trial 10902).¹ As pointed out in their letter, the management of the axilla after preoperative chemotherapy as well as in the primary surgery situation evokes discussion and is, therefore, not surprisingly the subject of clinical trials.

Since the introduction of the sentinel lymph node biopsy, the question has been raised whether, in the case of a positive sentinel node, axillary lymph node dissection (ALND) is still required or adjuvant radiotherapy alone to the axilla may be sufficient in terms of locoregional control. The EORTC Breast Cancer Group has recently started a randomized trial (After Mapping of the Axilla; Radiotherapy or Surgery [AMAROS]) that is addressing this particular question in patients with nonpalpable nodes. The results of this trial have to be awaited to give a definite answer to this problem.

As Lawrence et al state themselves, there is no doubt that ALND is indicated in patients with palpable nodal disease with or without preoperative chemotherapy. In clinically node-negative patients, especially with smaller tumor (T1a,b), ALND is debatable, and these patients should first undergo sentinel lymph node biopsy.

The possibility of nonsurgical management of the axilla after preoperative chemotherapy has been suggested before.² However, the conversion of axillary nodal status is poorly evaluated by palpation or, for instance, ultrasonography (negative predictive values of 39% to 44% and 44% to 58%, respectively).^3,4 In addition, other investigators,⁴ as well as us, found that axillary nodal status after preoperative chemotherapy remains an independent prognostic factor and thus may be crucial in determining subsequent treatment strategies.

Finally, approximately 30% of patients with axillary relapse will have uncontrollable disease.^5-7 The chance of axillary recurrence in initially untreated clinical node-negative patients (T1c/T2) is approximately 15%.^5-8 Therefore, approximately 5% of T1c/T2 cN0 patients who do not receive ALND will end up with uncontrollable disease. Therefore, we conclude that ALND cannot be routinely dismissed after preoperative chemotherapy because this will lead to understaging and may hamper locoregional control.

REFERENCES

1. van der Hage JA, van De Velde CJ, Julien JP, et al: Preoperative chemotherapy in primary operable breast cancer: Results from the European Organization for Research and Treatment of Cancer Trial 10902. J Clin Oncol 19: 4224-4237, 2001[Abstract/Free Full Text]

2. Kuerer HM, Sahin AA, Hunt KK, et al: Incidence and impact of documented eradication of breast cancer axillary lymph node metastases before surgery in patients treated with neoadjuvant chemotherapy. Ann Surg 230: 72-78, 1999[CrossRef][Medline]

3. Herrada J, Iyer RB, Atkinson EN, et al: Relative value of physical examination, mammography, and breast sonography in evaluating the size of the primary tumor and regional lymph node metastases in women receiving neoadjuvant chemotherapy for locally advanced breast carcinoma. Clin Cancer Res 3: 1565-1569, 1997[Abstract]

4. Rouzier R, Extra JM, Klijanienko J, et al: Incidence and prognostic significance of complete axillary downstaging after primary chemotherapy in breast cancer patients with t1 to t3 tumors and cytologically proven axillary metastatic lymph nodes. J Clin Oncol 20: 1304-1310, 2002[Abstract/Free Full Text]

5. Chua B, Ung O, Boyages J: Competing considerations in regional nodal treatment for early breast cancer. Breast J 8: 15-22, 2002[CrossRef][Medline]

6. Recht A, Pierce SM, Abner A, et al: Regional nodal failure after conservative surgery and radiotherapy for early-stage breast carcinoma. J Clin Oncol 9: 988-996, 1991[Abstract]

7. McKinna F, Gothard L, Ashley S, et al: Lymphatic relapse in women with early breast cancer: A difficult management problem. Eur J Cancer 35: 1065-1069, 1999[CrossRef][Medline]

8. Greco M, Agresti R, Cascinelli N, et al: Breast cancer patients treated without axillary surgery: Clinical implications and biologic analysis. Ann Surg 232: 1-7, 2000[CrossRef][Medline]

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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 Lawrence, G. Articles by van de Velde, C. J.H. Search for Related Content PubMed PubMed Citation Articles by Lawrence, G. Articles by van de Velde, C. J.H. Social Bookmarking                            What's this?