Neoadjuvant chemotherapy came into vogue in the seventies and eighties, spurred on by the success of organ preservation strategies in cancers such as laryngeal and rectal cancer. It used to be thought there are two potential benefits of neoadjuvant chemotherapy: downstaging a breast tumor so lesser surgery can be performed – lumpectomy instead of mastectomy, and to potentially treat early occult metastatic disease and to improve survival. The first goal can be successfully accomplished as has has been corroborated by large randomized studies but the second goal has not been proven to be accomplished by neaodjuvant chemotnerapy. In fact, studies do not show a survival approach for a neaodjuvant versus and adjuvant chemotherapy approach. However, more recently, with improving chemotherapy effectiveness, it became appreciated that response is a predictive tool that can be used to plan farther chemotherapy. The NOAH (NeOAdjuvant Herceptin) study demonstrated that trastuzumab in addition to chemotherapy not only doubled pCR rates compared with chemotherapy alone, but it also reduced the relapse rate by half. The TECHNO (Taxol Epirubicin Cyclophosphamide(Drug information on cyclophosphamide) Herceptin Neoadjuvant) study reported a significantly more favorable disease-free and overall survival for patients who achieved a pCR compared with those who did not. On the other hand, a recent pooled analysis of the German neoadjuvant studies investigated whether the prognostic impact of pCR on long-term outcome is equal to that of neoadjuvant chemotherapy and trastuzumab for patients with hormone receptor (HR)-positive and -negative tumors. In fact, whereas in 298 patients with HER2-positive/HR-negative tumors, a pCR was associated with a significantly better disease-free survival compared with no pCR (hazard ratio [HR] = 8.7, P < .001), no difference in outcome was seen in 356 patients with HER2-positive/HR-positive tumors (HR = 1.2; P = .543). Even without having an explanation for this observation, information about pCR should be used with caution in these triple-positive tumors unless other data sets provide different evidence. However, NCCN still only recommends neoadjuvant therapy for women in stage IIA or higher and who desire breast preservation.

R. Connoly et al, A Multidisciplinary Approach to Neoadjuvant Therapy for Primary Operable Breast Cancer ONCOLOGY. Vol. 24 No. 2 2010

NCCN, Breast Cancer, BREAST-12

B . Sousa et al, Neoadjuvant treatment for HER-2-positive and triple-negative breast cancers Ann Oncol Sep 1, 2012:x237-x242

Alfredo Berruti et al, International Expert Consensus on Primary Systemic Therapy in the Management of Early Breast Cancer: Highlights of the Fourth Symposium on Primary Systemic Therapy in the Management of Operable Breast Cancer, Cremona, Italy (2010) J Natl Cancer Inst Monogr Oct 1, 2011:147-151

For Lay version see here

Zoledronic Acid (Zometa) study presented at the ASCO 2008 Annual Meeting, demonstrated improved outcomes for pre-menopausal breast cancer patients receiving adjuvant endocrine therapy (some on tamoxifen), increasing disease-free survival by 36% and relapse-free survival by 35% for premenopausal patients who received adjuvant endocrine therapy for early breast cancer (Abstract LBA4). These researchers stated: “There is in fact an indication that zoledronic acid exerts its benefit through a variety of mechanisms, altogether obviously creating a tumor-hostile environment that helps kill micrometastases.”

However, the issue is not fully setted. A recent Cochrane guidelien disagrees. It underlines the fact that overall survival was not increased and that only 3 years followup was provided. It concludes:

• The routine use of either a GnRH analogue with tamoxifen or a GnRH analogue with anastrozole would not be considered standard of care in this setting ….
• The total duration of systemic therapy in this study was only three years, which would be considered suboptimal in most global settings.
• In this special advice report, we specifically define adjuvant endocrine therapy as the systemic therapy given after local therapy (i.e., surgery/radiotherapy) to help decrease the risk of the cancer recurring. This risk of recurrence is reflected through overall survival (OS), disease-free survival (time from randomization to local recurrence, contralateral carcinoma, distant metastasis, secondary carcinoma, and/or death), and or recurrence-free survival (time from randomization to local relapse, contralateral carcinoma, distant metastasis, and/or secondary carcinoma).

It also says the following. Care has been taken in the preparation of the information contained in this report. Nonetheless, any person seeking to apply or consult the report is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified clinician. Cancer Care Ontario makes no representation or guarantees of any kind whatsoever regarding the report content or use or application and disclaims any responsibility for its application or use in any way.

A 2012 review(Huang et al) concluded: “Treatment with zoledronic acid had a clear effect on fracture events, and it might contribute an important role for overall survival.

Huang W-W, Huang C, Liu J, Zheng H-Y, Lin L (2012) Zoledronic Acid as an Adjuvant Therapy in Patients with Breast Cancer: A Systematic Review and Meta-Analysis. PLoS ONE 7(7): e40783. doi:10.1371/journal.pone.0040783

Clemons M, Amir E, Haynes AE, Eisen A, Trudeau M. Zoledronic acid as adjuvant therapy in combination with adjuvant endocrine therapy for premenopausal women with early-stage hormone receptor positive breast cancer. Toronto (ON): Cancer Care Ontario (CCO); 2010 Jan 25. 18 p. (CED-CCO special advice report; no. 16).  [8 references]

Gnant, M. et al. Efficacy of Zoledronic acid in premenopausal women with breast cancer receiving adjuvant endocrine therapy – the ABCSG-12 trial. Presented at: the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Ill., 31 May – 2 June, 2008; Abstract LBA4.
subsequently published in hte NEJM Volume 360:679-691 February 12, 2009 Number 7

Beat Thuerlimann et al, Guidelines for the adjuvant treatment of postmenopausal women with endocrine-responsive breast cancer: Past, present and future recommendations European Journal of Cancer Volume 43, Issue 1, January 2007, Pages 46-52

Christian Seitz, Advances in the Medical Treatment of Prostate Cancer, Bladder Cancer, Renal Cell Cancer, and Benign Prostatic HyperplasiaRev Urol. 2003 Spring; 5(2): 90–110.
Highlights from the XVIIth Congress of the European Association of Urology, Birmingham, UK, February 23–26, 2002

Presribing information 2012

As part of a treatment regimen including doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel
With docetaxel and carboplatin
As a single agent following multi-modality anthracycline-based adjuvant therapy
Herceptin in combination with paclitaxel is approved for the first-line treatment of HER2-overexpressing metastatic breast cancer. Herceptin as a single agent is approved for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease.

Recent reports suggest that Herceptin can be used in the adjuvant setting for some early stage breast cancer patients. However these remain nonrandomized and speculative and the standard of care remains chemotherapy wth Herceptinfor those patients who can benefit form adjuvant therapy or no adjuvant chem for those with verye arly disease, not Herceptin alone.
National Comprehensive Cancer Network (NCCN). Breast cancer. Clinical Practice Guidelines in Oncology — v2.2005. Jenkintown, PA: NCCN; 2005.
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al.; Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353(16):1659-1672.
Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353(16):1673-1684.
Hortobagyi GN. Trastuzumab in the treatment of breast cancer. N Engl J Med. 2005;353(16):1734-1736.

The results of the study indicate that the addition of Avastin to chemotherapy did not reduce the risk of cancer recurrence. The same may turn out to be the case for breast cancer.

nccn.org, Breast Cancer

Roche Media Release. Phase III C-08 study of Avastin in early-stage colon cancer does not meet primary endpoint. Available at: http://www.roche.com/media/media_releases/med-cor-2009-04-22.htm.

Generic Aromasin is made by Roxane Laboratories, Inc., and Greenstone LLC. The version made by Greenstone is an “authorized generic,” which means that it is actually made by Pfizer and is actually the real, brand-name tablet but is packaged and sold as a generic.

There is no literature to support that brand is better then generic. All generic medications must undergo testing for bio-eqivalence before the U.S. Food and Drug Administration (FDA) decides if the generics are equivalent to the brand-name medications and assigns a rating to each one.

An “AB” rating means that the FDA has determined that a generic medication is equivalent to a brand-name medication. The generic exemestane currently available has an “AB” rating, meaning it should be equivalent to Aromasin.

Read the Layperson version here.

Biphopshonates are approved for treatment of osteoporosis and to prevent skeltal related events (fractures) in certain cancer patients with bone or other metastases. Clodronate, or ibandronate may delay or prevent bone metastases in patients with nonmetastatic breast cancer and are being studied for adjuvant therapy. In addition to the ABCSG-012 trial, which is reported below, the parallel-design Zometa®/Femara® Adjuvant Synergy Trials (Z-FAST and ZO-FAST in the U.S. and Europe, respectively) are investigating the benefit of immediate and delayed treatment with zoledronic acid (4 mg every 6 months) in postmenopausal women receiving adjuvant therapy with letrozole (2.5 mg/day) for early-stage hormone-receptor-positive breast cancer. Those trials will also enroll women in whom menopause has been induced by chemotherapy. The poposed trial is ongoing. Based on the results from early clinical trials, bisphosphonates appear to be effective for the prevention of fractures. Current consensus guidelines from the American Society of Clinical Oncology recommend the use of i.v. or oral bisphosphonate therapy in patients who develop T scores below -2.5 standard deviations from normal (osteoporosis) during adjuvant therapy for breast cancer.

NCT00127205, is a study of Zoledronate, Clodronate, or Ibandronate in Treating Women Who Have Undergone Surgery for Stage I, Stage II, or Stage III Breast Cancer. It is not yet known whether zoledronate is more effective than clodronate or ibandronate in treating breast cancer.

However,the Austrian Breast & Colorectal Cancer Study Group Trial 12 (ABCSG-21)reported that the addition of adjuvant Zometa® (zoledronic acid) to endocrine therapy for the treatment of hormone-positive, early breast cancer significantly improved progression-free and recurrence-free survival beyond the effects of endocrine therapy alone among premenopausal women. These results were recently presented as a late-breaking abstract at the 2008 annual American Society for Clinical Oncology (ASCO) meeting in Chicago, Illinois May 30 to June 2, 2008.

This was a multicenter, open-label Phase III study that included 1,803 premenopausal women with Stages I-II, hormone-positive breast cancer. Compared with hormone therapy alone, the addition of Zometa improved disease-free survival by 36% (p=0.01) and recurrence-free survival by 35% (p=0.015).

Researchers affiliated with the Austrian Breast & Colorectal Cancer Study Group Trial 12 (ABCSG-21) have reported that the addition of adjuvant Zometa® (zoledronic acid) to endocrine therapy for the treatment of hormone-positive, early breast cancer significantly improved progression-free and recurrence-free survival beyond the effects of endocrine therapy alone among premenopausal women. These results were recently presented as a late-breaking abstract at the 2008 annual American Society for Clinical Oncology (ASCO) meeting in Chicago, Illinois May 30 to June 2.

The current study, the Austrian Breast & Colorectal Cancer Study Group Trial 12 (ABCSG-21), was a multicenter, open-label Phase III study that included 1,803 premenopausal women with Stages I-II, hormone-positive breast cancer. Patients had fewer than 10 involved axillary lymph nodes. Following curative surgery and initiation of the gonadotropin-releasing hormone analog goserelin for ovarian suppression, patients were enrolled and randomized into one of four treatment groups: 1) Arimidex® (anastrozole) plus Zometa; 2) Arimidex alone; 3) Nolvadex® (tamoxifen) plus Zometa; 4) Nolvadex alone. Treatment was continued for three years; the median follow-up of the trial was five years. Disease-free survival in all treatment groups was the primary endpoint; recurrence-free survival, overall survival and safety were secondary endpoints. Bone-metastases-free survival was an exploratory endpoint of the trial.

Compared with hormone therapy alone, the addition of Zometa improved disease-free survival by 36% (p=0.01) and recurrence-free survival by 35% (p=0.015).

Patients treated with Zometa had a survival of 98% compared with 94% for the control group (p=0.10).
Patients treated with Zometa had a trend toward a lower risk of developing bone metastases (p>0.05).
Longer follow-up and a larger number of events are necessary to truly determine significance of overall survival and the risk of the development of bone metastases.

There were no reported cases of osteonecrosis of the jaw (ONJ); side effects were consistent with the known drug safety profile. These are among the first data to suggest that there is a specific anti-tumor effect of bisphosphonates in anadjuvant setting.

It is recommended that, if available, zoledronic acid (4 mg intravenously [over 15 minutes or longer] every 6 months [for 3 to 5 years]) or clodronate (1,600 mg/d orally [for 2 to 3 years]) be considered as adjuvant therapy for postmenopausal patients with breast cancer who are deemed candidates for adjuvant systemic therapy.
Sukhbinder Dhesy-Thind et al, Use of Adjuvant Bisphosphonates and Other Bone-Modifying Agents in Breast Cancer: A Cancer Care Ontario and American Society of Clinical Oncology Clinical Practice Guideline. Journal of Clinical Oncology 35, no. 18 (June 2017) 2062-2081.

Reid IR, Brown JP, Burckhardt P et al. Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med 2002;346:653–661

Gnant M, Hausmaninger H, Samonigg H et al. Changes in bone mineral density caused by anastrozole or tamoxifen in combination with goserelin (± zoledronate) as adjuvant treatment for hormone receptor-positive premenopausal breast cancer: results of a randomized multicenter trial. Presented at the 25th Annual San Antonio Breast Cancer Symposium, December 11–14, 2002, San Antonio, TX.

Saarto T, Blomqvist C, Valimaki M et al. Clodronate improves bone mineral density in post-menopausal breast cancer patients treated with adjuvant antioestrogens. Br J Cancer 1997;75:602–605

Allan Lipton Toward New Horizons: The Future of Bisphosphonate Therapy The Oncologist, Vol. 9, Suppl 4, 38–47, September 2004

The issues of toxicity are well worked out in both adjuvant and metastatic setting. In metastatic setting, dose dense chemo yilds higher response rates. Weekly administration of the drug paclitaxel (Taxol®) to patients with breast cancer that had spread to other parts of the body resulted in a higher response rate and a longer delay until patients’ disease progressed, compared with conventional administration of the drug every three weeks. A Phase III trial conducted in Germany studied 1284 patients under the age of 65 who had at least four lymph nodes containing metastatic cancer. Patients were assigned to receive either dose-dense chemotherapy or conventional treatment. At five years the relapse-free survival was 70 percent in the dose-dense arm, compared with 62 percent in the conventional-dose arm. Patients did seem to have a lower quality of life with the dose-dense method of treatment but recovered after a few months.

In terms of effectiveness, there is only one study, as cited above. NCCN lists dose-dense therapy. Although this one study has given promising results, it’s still too early to say if dose-dense chemotherapy is better than standard chemotherapy. However, there is expert consensus that it is not worse and not more toxic. It is thus equivalent to q 3 weeks non-dense therapy and should not be considered experimental or not med. necessary. The drugs themselves are FDA approved: “TAXOL is indicated for the adjuvant treatment of node-positive breast cancer administered sequentially to standard doxorubicin-containing combination chemotherapy.”

Citron ML et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup trial C9741/Cancer and Leukemia Group B trial 9741. J Clin Oncol 2003;21(7):1-9.

Jackisch C, Von Minckwitz G, Raab G, et al. Primary endpoint analysis of the GEPARDUO study — preoperative chemotherapy comparing dose-dense versus sequential Adriamycin/docetaxel combination in operable breast cancer. Program and abstracts of the 25th Annual San Antonio Breast Cancer Symposium; December 11-14, 2002; San Antonio, Texas. Abstract 152.

Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro CL, Ungaro P, Norton L, Winer E, Hudis C.Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840.J Clin Oncol. 2008 Apr 1;26(10):1642-9. Comment in: J Clin Oncol. 2008 Apr 1;26(10):1585-7.

nccn, breast cancer, BINVK-7, 2017

H. Joensuu et al, Adjuvant treatments for triple-negative breast cancers Ann Oncol (2012) 23 (suppl 6): vi40-vi45.