ESMO 2011 Report – Improving quality of life for breast cancer sufferers

by Dr Sunil Upadhyay – It would be difficult to imagine how one would treat breast cancer today if it was not for the work and leadership of Professor Umberto Veronesi from Milan. During his acceptance lecture for his life time achievements award at the EMCC in Stockholm he emphasized that from the beginning of his nearly 60 years of academic activity his main interest has been “Quality of Life” for his patients. He devoted almost all of his work trying to identify the best way to treat women with breast cancer so that their image and psychological integrity can be maintained without any negative impact on their therapy outcome.

During this long journey many lessons were learned and it resulted in a significant paradigm shift in the management of breast cancer. He commented that it has not been an easy journey because he had to face strong criticism, widespread challenges and repeated arguments but with constant persuasions and robust scientific evidence he was able to influence the change. As early as 1960, he came up with a new paradigm “from MAXIMUM TOLERABLE treatment to MINIMUM EFFECTIVE treatment”. It was a difficult shift from the popularly held belief by the then leaders in the field of cancer management. According to him, to achieve his goal, in 1969 he prepared a long plan called the ‘Milan QOL programme’ (1969-2010) which is actually still ongoing. The first phase of the plan consisted of conservation of the breast. In 1969, he was able to convince the late Prof Pierre Denoix from Paris (who developed TNM classification), the then chairman of the WHO international meeting of breast cancer investigators in Geneva to put “Possible clinical trial of techniques in the treatment of breast cancer which may lead to conservation of the breast” on the agenda. During that time radical Halsted mastectomy was the gold standard in the primary surgical management of breast cancer, thus his was a new idea and immediately rejected.

However, following prolonged discussion lasting over three days, Veronesi’s proposal was accepted and hence it was decided that local excision of the tumour plus axillary dissection and radical radiotherapy should be added as the third option along with the Halsted radical mastectomy or modified radical mastectomy, the other two options,  within the trial. Based on the observation that the majority of early stage breast tumours are confined to only one lobe of the breast for considerable length of time Prof Veronesi suggested that only one lobe (lobectomy /quadrantectomy) should be removed in patients with <2cm primary tumours and no palpable axillary lymph nodes. The final results published in NEJM¹ attracted front page headlines in the popular press all over the world. There were three local recurrences in the Halsted group and one in the quadrantectomy group. Actuarial curves showed no difference between the two groups in disease free survival or overall survival. The results provided level 1 evidence that mastectomy involved unnecessary mutilation in patients with early breast cancer. It led to women demanding breast conservation surgery instead of mastectomy with similar opportunity of cure. After a median follow-up of 20 years, the rate of death from all causes was 41.7% in the group that underwent breast-conserving surgery and 41.2% in the radical mastectomy group (p=1.0). The respective rates of death from breast cancer were 26.1% and 24.3% (p=0.8).² At almost the same time, renowned clinical cancer researcher Bernard Fisher and colleagues published NSABP B-04 results with similar conclusions.³ Thus breast conserving surgery followed by post operative radical radiotherapy became the gold standard therapy in early stage breast cancer patients.

Thereafter, he hypothesised that since it is the systemic disease which has a major negative impact on survival, removing the primary tumour alone with clear surgical margin (lumpectomy) could be the optimum therapy for the majority of early stage tumours. This led to the launch of Milan-II trial (1981-1983) comparing quadrantectomy versus lumpectomy. From 1985 to 1987, 705 patients were randomised and the published result showed that local relapses were fewer (5.3%) in quadrantectomy compared to lumpectomy (13.3%) group of patients despite post operative radiotherapy. However, despite higher local recurrence the overall survival was similar.⁴ It was concluded that the rate of local recurrence must have limited influence on survival because it is an anatomical event (occurring after surgery) whilst development of distant metastases leading to poor survival is a biological event (occurring before surgery) and that they are independent events. Unfortunately, local recurrence not only defeats the primary objective of breast conservation, but is also distressing leading to a negative effect on the psychological integrity of the individual. Therefore, careful assessment of the pathological specimen and generous surgical resection margin are of paramount importance⁵ followed by post-operative radiotherapy for a satisfactory local control.

Phase 2 of Prof Veronesi’s goals was conservation of the axillary lymph nodes because he was convinced that axillary clearance was not required in the majority of patients with early stage disease. However, simultaneous removal of the loco-regional lymph nodes had been implied in the surgical management of cancer for a century. In 1967, when he was the president of the international WHO melanoma group, he led a trial comparing surgical excision with (n=267) or without (n=286) immediate elective lymph node dissection in patients with stage 1 malignant melanoma of the limb with clinically negative lymph nodes. Ten years follow up results published showed identical survival.⁶ The statistical analysis showed no difference in survival between the two groups of patients, including subgroup analysis for sex, anatomical site, size and Clark’s level/Breslow’s thickness. The paper provoked worldwide reaction from the surgeons who had difficulty in breaking the dogma of prophylactic lymph node dissection. However, after extensive debate and discussion, including Donald Morton from California, sentinel lymph node biopsy using India blue ink was accepted as an intermediate compromise. Subsequently, the principle of lymphatic mapping and sentinel lymph node biopsy was expended and published by Giuliano A E et al.⁷ Almost at the same time, the Milan group were working on the use of radioactive isotope ⁹⁹Tc. After hard labour, they were able to identify the ideal size (200-400nm) of the colloidal protein molecule and label it with ⁹⁹Tc for use instead of the India blue dye. A randomised trial on its use under the umbrella of European Institute of Oncology was conducted in T1No cases (n=516) and surprisingly the SNB arm (dissection if the sentinel node positive) of patients showed better 10 year survival compared to axillary clearance arm (AD–23 deaths vs SN – 15 deaths; p=0.15).⁸ It has been hypothesised that the loss of the natural body immune protection due to complete removal of the axillary lymph nodes may have had some influence on the outcome. These results provided evidence to confirm that the SNB is a safe procedure in the management of breast cancer. It led to a trial on sentinel node micrometastases (<2mm) patients randomised to receive axillary node dissection versus observation and the 10-year survival was found to be similar between the two groups. Therefore, micrometastatic involvement of the sentinel axillary nodes does not require axillary clearance.

The other courageous trial conducted under his leadership by the Milan group has been the breast conservative surgery alone in clinically axillary node negative group of patients (T1No) randomised to receive no axillary treatment versus axillary radiotherapy (1993-1996). Again the 10-year survival results did not show any concerns hence it was concluded that in very early stage, good prognosis patient prophylactic axillary dissection could be avoided without undue risk. Of the over 20,000 sentinel lymph node biopsies done in Milan, in 3548 cases treated from 1996 to 2004 with negative axillary sentinel node biopsy and not submitted to axillary node dissection, following 11 years of follow up (median 48 months) it was found that only 31 (0.9%) axillary metastasis was observed when 213 (6%) was expected (false negative rate).⁹ The five-years’ overall survival for the whole series was 98%. Clearly, many occult axillary metastases do not progress to clinically overt metastases. This could be due to the effect of systemic therapy or lack of presence of cancer stem cells that have power to replicate and progress. Identification of cancer stem cells or their marker remains a challenge and requires further investigation. The ACOSOG Z0011 results provide strong support to these observations.¹⁰ These revolutionary results are practice-changing and provide evidence that selected groups of early stage patients do not benefit from axillary clearance despite positive sentinel nodes. It also provokes the question “does sentinel node biopsy have any role?” in the management of axilla. Currently, patients without clinical and ultrasound evidence of suspicious axillary nodes (T1No) are being randomised between sentinel node biopsy (dissection if positive) versus no axillary treatment within the IEO trial and the results should be available in the near future. Single fraction (21Gy) electron intra-operative radiotherapy (ELIOT trial) following breast conservative surgery is the other current obsession of Prof Veronesi and the preliminary results (Nov 2000 – Dec 2007; n=1306) are encouraging with identical distant relapse rate and overall survival for conventional external radiotherapy or intra-operative radiotherapy (unpublished).

References:

1. Veronesi U et al. New Eng J Med 1981 Jul 2; 305 (1): 6-11
2. Veronesi U et al. New Eng J Med 2002 Oct 17; 347: 1227-1232
3. Bernard Fisher et al. New Eng J Med 1985 March 14; 312: 665-673
4. Veronesi U et al. European J Cancer 1990; 26: 671-673
5. Holland R et al. JCO 1990; 8: 113-118
6. Veronesi U et al. NEJM 1977; 297: 627-630
7. Giuliano A E et al. Ann Surgery 1994; 220: 391-401
8. Veronesi U et al. NEJM 2003; 349: 546-553
9. Veronesi U et al.European J Cancer 2009; 45: 1381-1388
10. Giuliano A E et al. JAMA  2011 Feb 9; 6(305): 569-575