Breast cancer—Trials on conservative surgery

European Journal of Suryical Oncology 1995; 21:231-239

The Trials Section

In the two previous issues of the Journal, articles dealing with matters of general interest for clinical trials in surgical oncology were discussed. In this issue we commence the overviews of trials in specific solid tumours. Each edition will deal with a different topic. We start with breast cancer. The format for each cancer will be similar. An initial article will provide an overview of the recently completed trials in the specific malignancy. The main focus will be on European studies but important information arising from trials in other Continents will be included. Following this

review ongoing multi centre studies will be described which are of particular importance to surgeons..Some selection is inevitable because of space constraints. The final article will include a short discussion on topics which might usefully be addressed in future trials. The emphasis throughout these reviews will be to encourage individual surgeons, where appropriate, to randomize their patients into prospective trials. Joop van Dongen

Associate Editor

CLINICAL TRIALS

Breast cancer

Trials on conservative surgery Umberto Veronesi

European Institute of Oncology, Milan, Italy

Few advances in medical treatment have had such a difficult time in gaining acceptance as breast conservation for mammary carcinoma. The first randomized trials, conducted in the 1960s at Guy's hospital, London, showed a worrying increase in mortality rates among women treated by a breastconserving surgical procedure. The results, published in 1982, ~ made it ethically impossible for review boards to sanction further randomized trials to compare mastectomy with less radical surgical procedures. Fortunately, in 1969, a request for a new randomized multicentre trial, presented by the Milan Cancer Institute to the WHO Expert Committee, won approval after some considerable opposition and went ahead. This first Milan trial was completed by the end of the 1970s and its results published in 1981. They indicated that a breast-conserving treatment consisting of quadrantectomy, axillary dissection and radiotherapy was as safe as Halsted mastectomy) Subsequently many other trials, conducted throughout the world, confirmed this finding)-7 However many new questions arose from these early trials; some of which remain unanswered. Four main areas of uncertainty have been recognized. The first concerns the indications for breast conservation surgery: What is the maximum size of the primary consistent with safe conservation? What influence should site, histology and single lesion vs multifocality have on the decision to conserve? The second area of concern relates to surgical technique: Is lumpectomy adequate, or is a wider resection such as quadrantectomy safer? If the excision margins are involved, should a mastectomy always be performed or is a wider 0748-7983/95/030231 +09 $08.00/0

excision sufficient? Should excision width depend on histology: for example does presence of extensive intraductal component mandate a larger resection? Thirdly, there are questions about the role of radiotherapy: Is it always necessary or can it be avoided, perhaps in postmenopausal women or in those with minimal carcinomas? What is the best radiotherapy dosage? Is a boost always indicated, if so should it be from an external source or is radioactive interstitial implantation better? Fourthly we have the problem of treating local recurrences. Is mastectomy mandatory in all such cases or can re-excision be adequate? Faced with a local recurrence, should we view it as a sign of cancer aggression perhaps indicating systemic therapy, or is it more likely to be the result of an inadequate resection? All these uncertainties, symptomatic of the newness of conservation in breast cancer surgery, increase resistance to the idea and its adoption, particularly among more traditionalist surgeons, many of whom still insist that mastectomy is preferable for all cases of breast carcinoma. However, the many clinical trials started in the 1970s and 80s are now yielding results which are beginning to clarify many, if not most, of the issues broached above. For instance it now appears that, while having no influence on survival, a wider margin of resection correlates with a lower rate of recurrence.8'9With regard to positive resection margins, a reexcision seems adequate treatment in the majority of cases; ~° while the presence of an extensive intraductal component requires a very wide breast resection. ~-~3 As regards indications, many breast conservation trials were concerned only © 1995 W.B. Saunders Company Limited

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with small cancers ( < 2 . 5 cm greatest diameter), however the E O R T C study purposely randomized mainly T2 patients, and again showed no differences in survival between conservation and mastectomy. 6 Additionally, central location of the primary tumor is no longer a contraindication for breast conservation, since a central quadrantectomy that removes the nipple and areola is now a valid option, provided that a competent plastic reconstruction is performed.~4 There remains the problem o f what to do when there are two primary carcinomas. We believe that when these are in the same quadrant a quadrantectomy is possible, while things are much more problematic if they are distant. Radiotherapy is now recognized as an essential component of breast conservation, although further research is required to establish whether it may be safely avoided in postmenopausal women. ~5"~6 It has emerged, therefore, that extensive local surgery plus aggressive radiotherapy are necessary in order to keep the risk of local recurrence as low as possible. And this is important for several reasons. Firstly because recurrence is traumatic for the patient. Secondly because, as Lippmann pointed out recently, ~7 it is possible that a local recurrence carries an increased risk of dissemination and mortality. Thus, while most randomized trials fail to show any correlation between local recurrence rates and mortality, they do not have the power to detect modest increases in mortality as a result of inadequate local treatment. Perhaps a metaanalysis might detect such an effect. The need to reconcile wide surgical excision with good cosmetic outcome remains the most important problem in conservative breast surgery. Two possible ways forward are now under investigation. The first is to use neoadjuvant (preoperative) chemotherapy to reduce the size of the primary and hopefully also to reduce the risk of local recurrences with limited surgery. The second is the much more extensive use of plastic surgery, whose aim would be to simultaneously remodel both breasts. Using this approach, the initial resection can be more extensive as the contralaterai breast can be remodeled to m a t c h - - i n the same surgical session. Finally there is the problem of how best to treat local recurrences. In most cases a carefully performed re-excision will solve the local problem. Whether or not systemic therapy should be initiated remains a matter for discussion. In a recent study ~s we tried to identify characteristics o f local recurrence cases that indicated the need for additional treatment, compared with recurrences which were simply the result of inadequate surgery. We found that those occurring less than 2 years after original surgery, young age and presence of intravascular invasion were indicators of the need for additional treatrnent to forestall systemic disease. In conclusion, much progress has been made in treating breast c a n c e r - - t o the extent that we are now seeing decreased mortality for the disease in the USA. But there is still much to do. Leaving aside the huge question of prevention, the challenge that faces the surgeon is to tailor the 'severity' of the treatment ever more precisely to the aggressiveness of the disease. Advances on this front will depend on continuing large scale multicentric trials that evaluate the influence o f more subtle markers o f the biological behavior of breast cancer.

References

1. Atkins H, Hayward JL, Klugman D J, Wayte AB. Treatment of early breast cancer: a report after 10 years of clinical trial. Br M e d J 1.072; 2: 423-9. 2. Veronesi U, Saccozzi R, Del Vecchio M, Banff A, Clemente C, De Lena M, Gallus G, Greco M, Luini A, Marubini E, Muscolino G, Rilke F, Salvadori B, Zecchini A, Zucali R. Comparing radical mastectomy with quadrantectomy, axillary dissection, and radiotherapy in patients with small cancers of the breast. N En#l J Med 1981; 305: 6-11. 3. Sarrazin D, Le MG, Arriagada R, Contesso G, Fontaine F, Spielmann M, Rochard F, Le Chevalier T, Lacour J. Tenyear results of a randomized trial comparing a conservative treatment to mastectomy in early breast cancer. Radiother Oncol 1989; 14: 177-84. 4. Fisher B, Bauer M, Margolese R, Poisson R, Pilch Y, Redmond C, Fisher E, Wolmark N, Deutsch M, Montague E, Saffer E, Wickerham L, Lerner H, Glass A, Shibata H, Deckers P, Ketcham A, Oishi R, Russell I. Five-year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer. N Engl J Med 1985; 312: 665-73. 5. Blichert-Toft M, Rose C, Andersen JA, Overgaard M, Axelsson CK, Andersen KW, Mouridsen HT on behalf of the Danish Breast Cancer Cooperative Group. Danish randomized trial comparing breast conservation therapy with mastectomy: Six years of life-table analysis. J Natl Cancer blst Monogr 1992; 11: 19-25. 6. Van Dongen JA, Bartelink H, Fentiman IS, Lerut T, Mignolet F, Olthuis G, van der Schueren E, Sylvester R, Winter J, van Zijl K. Randomized Clinical Trial to assess the value of breastconserving therapy in stage I and II breast cancer, EORTC 10801 Trial. J Natl Cancer Inst Monogr 1992; 1I: 15-8. 7. Lichter AS, Lippman M, Danforth DN, Dangelo T, Steinberg SM, Demoss E, MacDonald HD, Reichter CM, Merino M, Swain SM, Cowan K. Mastectomy versus breast-conserving therapy in th6 treatment of stage I and II carcinoma of the breast: a randomized trial at the National Cancer Institute. J Clin Oncol 1992; 10: 976-83. 8. Veronesi U, Volterrani F, Luini A, Saccozzi R, Del Vecchio M, Zucali R, Galimberti V, Rasponi A, De Re E, Squicciarini P, Salvadori B. Quadrantectomy versus lumpectomy for small size breast cancer. Fur J Cancer 1990; 26: 671-3. 9. Ghossein NA, Alpert S, Barba J, Pressman P, Stacey P, Lorenz E, Shulman M, Sadarangani GJ. Breast cancer. Importance of adequate surgical excision prior to radiotherapy in the local control of breast cancer in patients treated conservatively. Arch Surg 1992; 127:411-5. 10. Veronesi U. How important is the assessment of resection margins in conservative surgery for breast cancer? Cancer 1994; 74: 1600-1. 11. Veronesi U, Farante G, Galimberti V, Greco M, Luini A, Sacchini V. Evaluation of resection margins after breast conservative surgery with monoclonal antibodies. Eur J Surg Oncol 1991; 17: 338-41. 12. Sehnitt SJ, Abner A, Gelman R, Connolly JL, Recht A, Duda RB, Eberlein TJ, Mayzel K, Silver B, Harris JR. The relationship between microscopic margins of resection and the risk of local recurrence in patients with breast cancer treated with breast-conserving surgery and radiation therapy. Cancer 1994; 6: 1746-51. 13. Holland R, Connolly JL, Gelman R, Mravunac M, Hendriks JHCL, Verbeek ALM, Schnitt SJ, Silver B, Boyages J, Harris JR. The presence of an extensive intraductal component following a limited excision correlates with prominent residual disease in the remainder of the breast. J Clin Oncol 1991; 8: 113--8. 14. Galimberti V, Zurrida S, Zanini V, Callegari M, Veronesi P, Catania S. Luini A, Greco M, Grisotti A. Central small size breast cancer: How to overcome the problem of nipple and areola involvement. Eur J Cancer 1993; 8: 1093-6. 15. Veronesi U, Luini A, Del Vecehio M, Greco M, Galimberti V, Merson M, Rilke F, Sacchini V, Saeeozzi R, Savio T, Zucali R,

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Zurrida S, Salvadori B. Radiotherapy after breast-preserving surgery in women with localized cancer of the breast. N Engl J Med 1992; 328: 1587-91. 16. The Uppsala-0rebro Breast Cancer Study Group. Sector resection with or without postoperative radiotherapy for stage I breast cancer: a randomized trial. J Natl Cancer lnst 1990; 82: 277-82. 17. Lippman ME. How should we manage breast cancer in the

breast, or buddy, can you paradigm? J Natl Cancer Inst 1995; 87: 3-4.

18. Veronesi U, Marubini E, Del Vecehio M, Manzari A, Andreola S, Greco M, Luini A, Merson M, Saccozzi R, Rilke F, Salvadori B. Local recurrences and distant metastases after conservative breast cancer treatments: partly independent events. J Natl Cancer Inst 1995; 87: 19-27.

Open randomized trials in the management of primary breast cancer Helen J. Stewart Ex-Director, Scottish Cancer Trials Office, Edinburgh, U K

There have been vast changes in the trial scene since 1948 when the first controlled randomized trial to assess the efficacy of a cancer treatment was commenced. The trial in question was conducted in the Christie Hospital, Manchester and was designed to assess the value of adjuvant ovarian ablation for primary breast cancer. Of the changes which have taken place since this trial, some have been gradual (e.g. the reduction in the extent of primary surgery) while others have happened more rapidly (e.g. the widespread use of adjuvant chemotherapy). Notable is the rekindling of interest in adjuvant ovarian ablation, completing this particular cycle of change. The development of effective anti-mitotic drugs and the anti-oestrogen tamoxifen in the 70s led to many randomized controlled trials of adjuvant systemic therapy. This, in turn, led to more trial centres to run trials with multi-centre participation and thus to larger studies. However, some of the initial reports which resulted were conflicting, due, in part, to variations in entry criteria and premature reporting. Keeping up-to-date with the many reports and applying the results to patient care became more difficult for those not directly involved. It was at this point that Richard Peto initiated the combined analysis of data from like trials and brought those involved together to form the Early Breast Cancer Trialists Collaborative Group (EBCTCG). The key results which came from this exercise are now well known, namely that adjuvant tamoxifen for 2 or more years can significantly reduce breast cancer mortality in postmenopausal women (by around 23%) and that multi-drug chemotherapy, principally CMF, produces a similar benefit to those in the younger age group. In 1990, further analysis after additional follow-up confirmed the earlier key results ~and, by analyses within sub-groups and indirect comparisons, more questions for direct comparison within further randomized trials were identified. These questions form the basis for many of the on-going trials today. A wider understanding of the methodology of randomized trials has developed in recent years and has influenced trial

design. Some of the important changes which have taken place are as follows. (1) The acceptance that simple variables, such as tumour size, number of involved nodes, menstrual status and steroid receptor content of the tumour, may be relevant to the choice of treatment and that late side effects and quality of life are important in the assessment of outcome.

(2) The need for collaborative effort when studying subgroups or rare types. This has led to an increase in multinational studies. (3) Greater appreciation of the need for large numbers in trials of adjuvant systemic therapy, especially when looking for additional gains from combining a second treatment with one of known benefit--for example the assessment of multimodality therapies. (4) The value ofthe 2 x 2 factorial design for trials by which two questions can be reliably answered from the numbers required to answer one question alone. (5) The advent of screening mammography with the resulting earlier diagnosis and increased identification of asymptomatic non-invasive breast cancers. Since that first trial many thousands of women presenting with early breast cancer world-wide have had their treatment determined randomly and it has become increasingly difficult to keep track of the constantly changing scene as new trials are opened and others are closed or abandoned. No listing is completely up-to-date, even on a national basis. F o r this review I have considered only trials being conducted in North America and Europe, using for reference current PDQ, 2 EORTC and EBCTCG registers of trials not known to have closed. I know that errors of omission and commission have occurred in so doing but I think none-the-less that this allows the creation of a reasonably accurate overall picture. There are few trials in which the control group receive no systemic therapy. This can only be justified nowadays when the prognosis is exceptionally good or the pail-