Cancer Treatment Today » Breast Cancer and GYN Cancers

Breast Cancer/Doxil – pro

M Levin, MD — Tue, 04 Sep 2012 14:52:34 +0000

Pegylated liposomal doxorubicin is currently approved in the U.S. for the treatment of platinum-refractory metastatic ovarian cancer and AIDS-related Kaposi’s sarcoma.DOXIL (doxorubicin hcl liposome injection) in combination with bortezomib is indicated for the treatment of patients with multiple myeloma who have not previously received bortezomib and have received at least one prior therapy. It is also has been evaluated in several other tumor types, including breast cancer, non-Hodgkin’s lymphoma, and gynecologic malignancies. When compared with other liposomal anthracycline formulations, pegylated liposomal doxorubicin is the most extensively studied in patients with metastatic breast cancer(MBC). Pegylated liposomal doxorubicin has demonstrated antitumor activity and safety in patients with MBC, leading to its recent approval in the European Union as monotherapy for MBC in patients who have greater cardiac risks, in addition to its compendial listing in the U.S. for patients with MBC. The efficacy and safety of pegylated liposomal doxorubicin as single-agent therapy for MBC have been investigated in two phase II trials . In the first study, a total of 71 patients with stage IV breast cancer received pegylated liposomal doxorubicin at doses of 45-60 mg/m2 every 3-4 weeks for a maximum of six cycles; all patients had received prior nonanthracycline-based chemotherapy . The overall response rate was 31%, and treatment was generally well tolerated. Grade 3 or 4 neutropenia and mucositis were noted in 27% and 32% of patients, respectively; alopecia, cardiotoxicity, and nausea and vomiting were uncommon. Although skin toxicity occurred in 25% of cycles in patients receiving 60 mg/m2 every 3 weeks, the incidence was much lower at doses of 45 mg/m2 every 4 weeks, with only 5% of treatment cycles affected. Two phase III studies have compared the efficacy and safety of pegylated liposomal doxorubicin with those of other treatment regimens. Wigler and colleagues compared the efficacy and safety of pegylated liposomal doxorubicin with those of conventional doxorubicin as first-line therapy in patients with advanced MBC. A total of 509 women received 1-hour infusions of either pegylated liposomal doxorubicin, 50 mg/m2 once every 4 weeks, or conventional doxorubicin, 60 mg/m2 once every 3 weeks. Primary end points were progression-free survival and cardiac safety, while secondary end points included overall survival, response rate, and safety. The median progression-free survival was similar in both treatment groups: 6.9 months in patients receiving pegylated liposomal doxorubicin versus 7.8 months in patients receiving conventional doxorubicin (p = 0.99). Likewise, overall survival was 20.1 months for patients receiving pegylated liposomal doxorubicin, compared with 22.0 months in those receiving the conventional formulation. The incidences of alopecia, myelosuppression, and nausea and vomiting were lower in patients treated with pegylated liposomal doxorubicin than in patients treated with conventional doxorubicin. Perhaps most notably, pegylated liposomal doxorubicin was associated with a significantly lower incidence of cardiotoxicity, even at higher cumulative doses (p < 0.001). In another phase III study involving 301 patients with advanced MBC who had failed a prior taxane-containing regimen, Keller and colleagues compared pegylated liposomal doxorubicin, 50 mg/m2 every 4 weeks, with the European standard of treatment, either vinorelbine, 30 mg/m2 once weekly, or mitomycin C, 10 mg/m2 on days 1 and 28, plus vinblastine, 5 mg/m2 on days 1, 14, 28, and 42 every 6-8 weeks. The primary end point was progression-free survival; secondary end points included overall survival, response rate, and toxicity.
In that study, pegylated liposomal doxorubicin demonstrated efficacy similar to that of the comparator regimens.

A 2013 reveiw concluded: “In patients with metastatic breast cancer, liposomal anthracyclines have proven to be as effective and less toxic when compared face to face with conventional anthracyclines, allowing a longer period of treatment and a higher cumulative dose of the anthracyclines. The combined analysis of available data indicates an overall reduction in risk for both cardiotoxicity (RR = 0.38, ) and clinical heart failure (RR = 0.20, ). The safety of liposomal anthracyclines endorsed its use in patients with some cardiac risk factors.

In HER2-positive breast cancer, the addition of trastuzumab to chemotherapy significantly increased response rate, progression-free survival, and overall survival. Initial studies demonstrated synergy when trastuzumab was combined with anthracyclines, but their excessive cardiac toxicity limited their use and nonanthracycline therapeutic strategies were designed.

Liposomal anthracyclines have proven to be effective and safe when combined with trastuzumab both in advanced and early breast cancer. Of particular interest is the use of the combination of liposomal anthracyclines plus trastuzumab in patients with early and HER2-overexpressing breast cancer, as this is probably the subgroup that would benefit most from a treatment with anthracyclines. The potential clinical benefit of anthracyclines in this setting should be investigated in a clinical trial comparing a regimen with liposomal anthracyclines versus a nonanthracyclines combination. ”

Juan Lao et al, Liposomal Doxorubicin in the Treatment of Breast Cancer Patients: A Review, Journal of Drug Delivery
Volume 2013 (2013), Journal of Drug Delivery
, Article ID 456409, 12 pages

http://dx.doi.org/10.1155/2013/456409

Edgardo Rivera Liposomal Anthracyclines in Metastatic Breast Cancer: Clinical Update The Oncologist, Vol. 8, Suppl 2, 3–9, August 2003

Wigler N, O’Brien M, Rosso R et al. Reduced cardiac toxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin (CAELYXTM/Doxil) vs. doxorubicin for first-line treatment of metastatic breast cancer. Poster presented at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, Florida, May 18-21, 2002.

Continuing Herceptin past relapse – pro

M Levin, MD — Tue, 04 Sep 2012 14:38:35 +0000

The issue of continuing Herceptin is complex but there is little firm evidence to support this practice. The current practice is supported solely by a retrospective chart review of 1000 women presented in 2002. However, NCCN currently on p. BINV-20 of its 2011 breast cqncer guideline says in a note that continuing trastuzumab after progression on first-line therapy is a option. Optimal duration is unknown.

Whether to continue trastuzumab after objective evidence of disease progression or not is an important unanswered clinical question for women with metastatic disease. This question is also relevant for those who relapse after adjuvant trastuzumab-containing therapy. Unfortunately, there is little evidence to guide decision-making. The modest toxicity and the possible, but unproven, benefit from the continued use of trastuzumab may account for the currently wide spread practice of continued administration of this drug after progression. However, there is no convincing evidence to support the use of extended trastuzumab therapy after progression. At least two randomized trials with no trastuzumab in the control arms were attempted but failed to accrue patients. In the absence of results from a randomized clinical trial, a central registry program that collects information longitudinally from a large number of patients with HER-2 positive breast cancer during the course of their disease was initiated (RegistHER, www.registher.com ) to learn about the long term side effects and benefits of prolonged trastuzumab therapy. The anticipated introduction of second generation HER2-targeted agents into the clinic also raises a new question; will switching to these agents be more effective than continuation of trastuzumab? Clinical trials are currently planned to address the question prospectively.

J. Mackey et al.Herceptin can be continued even after disease progression without worse side effects and with possible benefits, ASCO Program/Proceedings, May 2002, abstract #207

Pusztai, Lajos1; Esteva, Francisco, Continued Use of Trastuzumab (Herceptin) after Progression on Prior Trastuzumab Therapy in HER-2-Positive Metastatic Breast Cancer, Cancer Investigation, Volume 24, Number 2, March 2006, pp. 187-191(5)

Prophylactic mastectomy – pro

M Levin, MD — Tue, 04 Sep 2012 14:37:05 +0000

Prophylactic total or simple mastectomy, not subcutaneous mastectomy, for patients at high risk of breast cancer is a difficult issue in that it involves the determination of risk in an individual patient, a separate determination of what level of risk is high enough to justify the extreme choice of prophylactic mastectomy, and assurance from scientific studies in the medical literature that this procedure does result in a reduction of breast cancer occurrence. In addition, the approach among surgeons differs from that of medical oncologists. Even if the risk can be estimated, the decision to proceed with a prophylactic mastectomy will be largely patient driven, dependent on whether the patient feels comfortable living with the estimated risk and how she values the psychosexual function of the breast. Although the definition of “high risk” is somewhat arbitrary, the consensus of opinion is that prophylactic mastectomy may be considered only in patients at high risk of breast cancer with a demonstrated BRCA gene mutation or a life-long risk level in excess of 25-30%.

BRCA1 and BRCA2 may be responsible for only 5% to 10% of all breast cancers and about 20% of breast cancers diagnosed in women under age 45. About 50%-60% of women with inherited BRCA1 or BRCA2 mutations will develop breast cancer by the age of 70. Provisional recommendations by the Cancer Genetics Studies Consortium for follow up of individuals with BRCA1 or BRCA2 mutations involve counseling and early breast cancer screening, including annual mammography and clinical breast examination beginning at age 25 to 35 years, and monthly breast self-examination beginning at age 18 to 21 years. A few recent studies have shown that among women who test positive for a BRCA1 or BRCA2 gene mutation, prophylactic surgery at a young age substantially improves survival.

Even among women with breast cancer in their families, the tests for BRCA1 and BRCA2 may be negative 90% of the time, unless a mutation has been previously identified in the family. A negative BRCA1 and BRCA2 test result would mean that a woman still faces the same risk as the general population of developing sporadic, non-inherited breast cancer. However, in such BRCA negative patients, other significant risk factors come into play. A personal history of invasive breast cancer or lobular carcinoma in situ increases the risk of developing a new breast cancer in any remaining breast tissue in either breast by 0.5% to 1.0% per year.

The degree of reduction of risk of breast cancer with prophylactic mastectomy is not well documented in the literature. All studies were observational studies with some methodological limitations; no randomized trials exist. All studies reporting on incidence of breast cancer and disease-specific mortality reported reductions after Bilateral Prophylactin MMastectomies including those with BRCA1 and 2 mutations. Nine studies assessed psychosocial measures; most reported high levels of satisfaction with the decision to have prophylactic mastectomy (PM) but more variable satisfaction with cosmetic results. Worry over breast cancer was significantly reduced after BPM when compared both to baseline worry levels and to the groups who opted for surveillance rather than BPM.

For Contralateral PM, studies consistently reported reductions in contralateral incidence of breast cancer but were inconsistent about improvements in disease-specific survival. Only one study attempted to control for multiple differences between intervention groups; this study showed no overall survival advantage for CPM at 15 years. Two case series were exclusively focused on adverse events from prophylactic mastectomy with reconstruction; both reported rates of unanticipated re-operations from 30% to 49%.

While published observational studies demonstrated that BPM was effective in reducing both the incidence of, and death from, breast cancer, more rigorous prospective studies (ideally randomized trials) are needed. BPM should be considered only among those at very high risk of disease. There is insufficient evidence that CPM improves survival.

American Society of Surgical Oncology recommends prophylactic mastectomies for patients a HIgh RIsk. This is how it defines High Risk: 1

BRCA mutations or other genetic susceptibility genes
•Strong family history with no demonstrable mutation
•Histologic risk factors

NCCN also recommends prophylactic mastectomies only for high risk women. It its definition it is those who have a known genetic mutation. 2

1. Position Statement on Prophylactic Mastectomy, http://www.surgonc.org/resources/consensus-statements/position-statement-on-prophylactic-mastectomy 2007.

2.NCCN, BRISK-6, 2015

Tuttle TM¹, Jarosek S, Habermann EB, Arrington A, Abraham A, Morris TJ, Virnig BAIncreasing rates of contralateral prophylactic mastectomy among patients with ductal carcinoma in situ.J Clin Oncol. 2009 Mar 20;27(9):1362-7

Lostumbo L, Carbine N, Wallace J, Ezzo J. Prophylactic mastectomy for the prevention of breast cancer. Cochrane Database Syst Rev. 2004;(3).
Sakorafas GH, Tsiotou AG. Prophylactic mastectomy; evolving perspectives. Eur J Cancer. 2000;36(5):567-578.
Solomon JS, Brunicardi CF, Friedman JD. Evaluation and treatment of BRCA-positive patients. Plast Reconstr Surg. 2000;105(2):714-719.

For BRCA positive women see here

Oxaliplatin for ovarian cancer – pro

M Levin, MD — Tue, 04 Sep 2012 14:34:21 +0000

Most studies of oxaliplatin in advanced ovarian cancer have been conducted after relapse, or in patients refractory to other platinum compounds. Oxaliplatin monotherapy in this patient population produced response rates ranging from 16 to 27%. Missetti et al showd in 2000 that response rates were similar to those obtained with paclitaxel monotherapy (16 vs 17%).

Guidelines from NCCN state that oxaliplatin is an acceptable alternative chemotherapeutic regimen for recurrent epithelial ovarian cancer for Stage II, III, and IV patients with partial responses to their primary paclitaxel and platinum-based chemotherapeutic regimens. The guidelines note that oxaliplatin has been demonstrated to be active in recurrent epithelial ovarian cancer.

There are severalphase II studies that combine oxaliplatin with otehr drugs, such as Doxil, Xeloda and Avastin or another taxane.

Misset J, Vennin P, Chollet P, et al. Multicenter phase II/III study of oxaliplatin plus cyclophoshamide (C) [OXC] versus cisplatin (P)plus cyclophoshamide [CPC] in advanced chemonaive ovarian cancer (AOC) patients: Final results [abstract no. 1502]. 36th ProcAm Soc Clin Oncol; 2000 May 20-23; Denver

Viens P, Petit T, Yovine A, et al. A phase II study of a paclitaxel and oxaliplatin combination in platinum-sensitive recurrent advanced ovarian cancer patients. Ann Oncol. 2006;17(3):429-436.
Nicoletto MO, Falci C, Pianalto D, et al. Phase II study of pegylated liposomal doxorubicin and oxaliplatin in relapsed advanced ovarian cancer. Gynecol Oncol. 2006;100(2):318-323.
Misset JL, Vennin P, Chollet PH, et al. Multicenter phase II-III study of oxaliplatin plus cyclophosphamide vs. cisplatin plus cyclophosphamide in chemonaive advanced ovarian cancer patients. Ann Oncol. 2001;12(10):1411-1415.
Piccart MJ, Green JA, Lacave AJ, et al. Oxaliplatin or paclitaxel in patients with platinum-pretreated advanced ovarian cancer: A randomized phase II study of the European Organization for Research and Treatment of Cancer Gynecology Group. J Clin Oncol. 2000;18(6):1193-1202.
National Comprehensive Cancer Network (NCCN). Ovarian cancer. Clinical Practice Guidelines in Oncology OV-E, 2013

J. Alexandre et al,Mucinous advanced epithelial ovarian carcinoma: clinical presentation and sensitivity to platinum-paclitaxel-based chemotherapy, the GINECO experience Ann Oncol Dec 1, 2010:2377-2381

Biphopsphonates for osteoporosis in breast cancer – pro

M Levin, MD — Tue, 04 Sep 2012 14:30:50 +0000

Prolia or Zometa can be used for prevention or treatment of Osteoporosis1. , Osteoporosis is often a comorbid condition in patients with breast cancer. The antineoplastic therapy for breast cancer can itself have adverse effects on bone. Chemotherapy can have direct negative effects on bone mineral density, as can the glucocorticoids used as antiemetics and premedications. Adjuvant chemotherapy can cause premature menopause and increased risk for osteoporosis. Hormonal treatmetn with aromatase inhibitore can cause or aggravate osteoporosis. Osteoporosis can be both prevented and treated with bisphosphonates.

As an update to their earlier publication, the American Society of Clinical Oncology (ASCO) has recently published clinical practice guidelines on the role of bisphosphonates and bone health issues for women with breast cancer. The guidelines committee stated, “Oncology professionals, especially medical oncologists, need to take an expanded role in the routine and regular assessment of the osteoporosis risk in women with breast cancer. 2 ” All patients initiating AIs need advice regarding exercise, calcium/vitamin D supplements, baseline BMD monitoring (when available), and bone-directed therapy if T-score <2.0 or at least two fracture risk factors were observed. Patients with T-score > 2.0 and no risk factors should be managed based on BMD loss during years 12. Unsatisfactory compliance/decreasing BMD after 1224 months on oral bisphosphonates should trigger a switch to i.v. bisphosphonate. 3

Prolia is indicated as a treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer.

See entry on Xgeva.
P. Hadji et al, Management of aromatase inhibitor-associated bone loss in postmenopausal women with breast cancer: practical guidance for prevention and treatment Ann Oncol (2011)

Burstein HJ, Temin S, Anderson H, et al: Adjuvant endocrine therapy for women with hormone receptorpositive breast cancer: American Society of Clinical Oncology clinical practice guideline focused update. J Clin Oncol 32:2255-2269, 2014.

GRETCHEN L. JOHNSON, Denosumab (Prolia) for Treatment of Postmenopausal Osteoporosis. Am Fam Physician. 2012 Feb 15;85(4):334-336.

Boonen S, Adachi JD, Cummings SR, et al. Treatment with denosumab reduces the incidence of new vertebral and hip fractures in postmenopausal women at high risk.J Clin Endocrinol Metab2011; 96:1727-36.

Prolia, Prescribing Infomration 2017
P. Hadji et al, Management of aromatase inhibitor-associated bone loss in postmenopausal women with breast cancer: practical guidance for prevention and treatment Ann Oncol (2011)

GRETCHEN L. JOHNSON, Denosumab (Prolia) for Treatment of Postmenopausal Osteoporosis. Am Fam Physician. 2012 Feb 15;85(4):334-336.

Prolia, Prescribing Infomration 2017

PP. Hadji et al, Management of aromatase inhibitor-associated bone loss in postmenopausal women with breast cancer: practical guidance for prevention and treatment Ann Oncol (2011)

GRETCHEN L. JOHNSON, Denosumab (Prolia) for Treatment of Postmenopausal Osteoporosis. Am Fam Physician. 2012 Feb 15;85(4):334-336.

Prolia, Prescribing Infomration 2017

Capecitabine/gemcitabine combination – pro

M Levin, MD — Tue, 04 Sep 2012 14:28:58 +0000

cCapecitabine (Xeloda®; Hoffmann-La Roche Inc., Nutley, NJ) is an orally administered fluoropyrimidine carbamate used to treat breast and colorectal cancer. Readily absorbed by the gastrointestinal tract, capecitabine is metabolized by the enzyme carboxylesterase in the liver, where it is converted to 5′ deoxy-5-fluorocytidine (5′ DFCR), which is then converted by the enzyme cytidine deaminase to 5′ deoxy-5-fluorouridine (5′ DFUR). As a result, orally administered capecitabine enables physicians treating breast cancer to mimic the effect of continuous infusion 5-FU but in a convenient outpatient setting without the complications and costs associated with infusion pumps and parenteral therapies. Capecitabine was approved in 1998 by the U.S. Food and Drug Administration as a single agent for patients with metastatic breast cancer that is resistant to both paclitaxel and anthracyclines, and for those with breast cancer resistant to paclitaxel and for whom further anthracycline therapy is contraindicated. Capecitabine is also approved for combination therapy with docetaxel for the treatment of patients with metastatic breast cancer in whom prior anthracycline-based therapy has failed.

There is phase II data on combining capecitabine with gemcitabine. I was able to find three sudies that claim effectiveness for this combination.

Lambea J, Isla D, Saenz-Cusi A, Escudero P, Tres A. et al, Gemcitabine/capecitabine in patients with metastatic breast cancer pretreated with anthracyclines and taxanes. Clin Breast Cancer. 2005 Jun;6(2):158-62. Andres R, Mayordomo J, Isla D et al. Capecitabine plus gemcitabine is an active combination for patients with metastatic breast cancer refractory to anthracyclines and taxanes. Proc Am Soc Clin Oncol 2003;22:89. Manga G, Lopez-Criado P, Mendez M et al. Gemcitabine (G) plus capecitabine (C) in previously treated metastatic breast cancer (MBC) patients: results from a phase II GOTI trial. Proc Am Soc Clin Oncol 2003;22:66.

Ifosfamide for recurrent ovarian cancer – pro

M Levin, MD — Tue, 04 Sep 2012 14:21:50 +0000

Recurrent ovarian cancer is a difficult clincal problem; fortunately, a number of options are available. For patients whose disease is platinum-refractory (i.e., with disease that has progressed while on a platinum regimen or that has recurred shortly after completion of a platinum-containing regimen), treatment with paclitaxel (Taxol) historically provided the first agent with consistent activity in these patients and should be considered. Other options include tamoxifen, Doxil, vinorelbine, gemcitabine, Xeloda, top[otecan, hexamethylamine,methotrexate.

Modest activity has been demonstrated in patients with epithelial ovarian cancer, including disease that is platinum-refractory. A Gynecologic Oncology Group study demonstrated 3 clinical complete responses and 5 partial responses (overall response rate was 20%) in 41 evaluable patients who were either refractory to platinum or who had relapsed following platinum-based chemotherapy. Toxic effects include myelosuppression, nephrotoxicity, hemorrhagic cystitis, and toxic encephalopathy. Other phase II studies confirm the activity of ifosfamide in patients with epithelial ovarian cancer. In one phase II study, 7 objective responses were observed in 52 patients (objective response rate was 13.5%). Of the 7 patients who responded, 5 had tumors that were platinum-refractory.

Since then 7 or 8 phase II trials, singly or in combination have been performed. most f them in the late 1990′s. The drug is mentioned in the reviews of treatment of recurrent ovarian cancer. As an older agent, most of the experience with ifosfamide has been in patients previously treated with a combination of platinum and cyclophosphamide, prior to the incorporation of paclitaxel. It has been suggested that the current second-line activity of ifosfamide might be enhanced as a consequence of a reduction in the use of cyclophosphamide during initial therapy of ovarian cancer. However, a recently reported trial of single-agent ifosfamide in patients refractory to both platinum and paclitaxel has revealed an objective response rate of only 15%, similar to that achieved in patients previously treated with cyclophosphamide.

Ifosfamide has a number of important toxicities to be considered in the ovarian cancer population, including neutropenia, renal dysfunction, injury to the urothelium (hemorrhagic cystitis), and reversible central nervous system dysfunction. Risk for these toxicities is increased in elderly patients with renal dysfunction and low serum albumin, which are common findings in recurrent ovarian cancer. The drug also has the disadvantage of being administered over multiple days, or requiring a 24-h intravenous infusion.

The drug is not FDA approved. This is off-label use. However, it is mentioned by NCCN and NCI-PDQ. It is listed in ACCC but not other compendia. The documents reviewed did not include Plan defintions or language. However, applying general criteria, this treatment would appear to be suffciently justified by multiple phase II studies, listing in standard guidelines and the clinical situation to warrant approval.

V. Linasmita, S. Wilailak, S. Srisupundit, S. Tangtrakul, S. Bullangpoti, N. Israngura (1997) Ifosfamide/mesna plus adriamycin as salvage therapy of advanced epithelial ovarian cancer International Journal of Gynecological Cancer 7 (5), 388–391.

Hogberg T, Glimelius B, Nygren P; SBU-group. Swedish Council of Technology Assessment in Health Care. Systematic overview of chemotherapy effects in ovarian cancer. Acta Oncol. 2001;40(2-3):340-60.

Thomas J Herzog, Bhavana Pothuri
Ovarian cancer: a focus on management of recurrent disease Nature Clinical Practice Oncology (2006) 3, 604-611

Maurie Markman, Michael A. Bookman Second-Line Treatment of Ovarian Cancer The Oncologist, Vol. 5, No. 1, 26-35, February 2000

Sutton GP, Blessing JA, Homesley HD et al. Phase II trial of ifosfamide and mesna in advanced ovarian carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 1989;7:1672-1676.

Sorensen P, Pfeiffer P, Bertelsen K. A phase 2 trial of ifosfamide/mesna as salvage therapy in patients with ovarian cancer refractory to or relapsing after prior platinum-containing chemotherapy. Gynecol Oncol 1995;56:75-78.

Markman M, Hakes T, Reichman B et al. Ifosfamide and mesna in previously treated advanced epithelial ovarian cancer: activity in platinum resistant disease. J Clin Oncol 1991;10:243-248.

Markman M, Kennedy A, Sutton G et al. Phase 2 trial of single agent ifosfamide/mesna in patients with platinum/paclitaxel refractory ovarian cancer who have not previously been treated with an alkylating agent. Gynecol Oncol 1998;70:272-274.

Zoladex tamoxifen for adjuvant premenopausal breast cancer – pro

M Levin, MD — Tue, 04 Sep 2012 14:19:32 +0000

Whether chemotherapy or endocrine therapy is better for premenopausal women in the adjuvant setting remains an open question. An older study demonstrated that, as adjuvant treatment for node-negative or node-positive, ER+ breast cancer, combination tamoxifen/goserelin treatment reduced the number of recurrences when compared with 6 cycles of CMF in premenopausal women. Most significant was the decrease in local recurrence associated with tamoxifen/goserelin. It is fair to say that several studies demostrate that treatment with goserelin leads to a significant improvement in disease-free survival and reduction of contralateral breast cancer in premenopausal women receiving adjuvant therapy for resected stage I/II breast cancer. Also, a trend towards improvement in overall survival was observed.

The use of ovarian suppression by means of LHRH analogues has been investigated primarily in pre- and peri-menopausal women. The rationale of these trials has included an attempt to achieve ovarian suppression with subsequent inhibition of tumor cell proliferation. Goserelin is a synthetic decapeptide analogue of the naturally occurring LHRH, which, following chronic subcutaneous administration, leads to a reduction in concentrations of LH (luteinizing hormone) and FSH (follicle stimulating hormone) and then to a decrease in circulating estrogen concentrations.

NCCN lists combined ovarian supression as a recommended option for premenopauseal women.

Jonat W, Kaufmann M, Sauerbrei W et al. Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: the Zoladex Early Breast Cancer Research Association Study. J Clin Oncol 2002;20:4628–4635.

Kaufmann M, Jonat W, Blamey R etal. Survival analyses from the ZEBRA study. Goserelin (Zoladex) versus CMF in premenopausal women with node-positive breast cancer. Eur J Cancer 2003;39:1711–1717.

Schmid P, Untch M, Wallwiener D et al. Cyclophosphamide, methotrexate and fluorouracil (CMF) versus hormonal ablation with leuprorelin acetate as adjuvant treatment of node-positive, premenopausal breast cancer patients: preliminary results of the TABLE-study (Takeda Adjuvant Breast cancer study with Leuprorelin Acetate). Anticancer Res 2002;22:2325–2332.

Castiglione-Gertsch M, O3Neill A, Price KN et al. Adjuvant chemotherapy followed by goserelin versus either modality alone for premenopausal lymph node-negative breast cancer: a randomized trial. J Natl Cancer Inst 2003;95:1833–1846

Mariantonietta Colozza, Evandro de Azambuja, Fatima Cardoso, Chantal Bernard, Martine J. Piccart, Breast Cancer: Achievements in Adjuvant Systemic Therapies in the Pre-Genomic Era Oncologist, Vol. 11, No. 2, 111-125, February 2006

Pritchard KI.Ovarian suppression/ablation in premenopausal ER-positive breast cancer patients. Issues and recommendations.Oncology (Williston Park). 2009 Jan;23(1):27-33

Gemcitabine/vinorelbine for metastatic beast cancer – pro

M Levin, MD — Tue, 04 Sep 2012 14:18:05 +0000

Chemotherapy remains a mainstay in the treatment of breast cancer. Anthracyclines and taxanes are two classes of chemotherapy agents that are commonly used to treat breast cancer. Because treatment options are limited for patients whose cancer recurs following use of anthracyclines and taxanes, researchers continue to evaluate newer and different chemotherapy combinations in an effort to improve the duration of survival for these patients.

According to an article recently published in Lancet Oncology, the addition of the chemotherapy agent Gemzar® (gemcitabine) to Navelbine® (vinorelbine) improves progression-free survival, but not overall survival, compared with Navelbine alone in women with breast cancer whose disease has progressed following prior chemotherapy.

Researchers from Spain recently conducted a Phase III trial referred to as the GEICAM trial to compare different chemotherapy regimens in women with recurrent breast cancer. This trial included 252 women who had previously been treated with anthracyclines and taxanes and had experienced a recurrence. One group was treated with Gemzar and Navelbine, while the other group was treated with Navelbine.

Median progression-free survival was longer at six months for patients treated with Gemzar/Navelbine compared with four months for those treated with Navelbine only.
Overall survival was approximately 16 months for both groups of patients.
Anticancer responses were 36% for patients treated with Gemzar/Navelbine and 26% for patients treated with Navelbine. The researchers concluded that the addition of Gemzar to Navelbine improves progression-free survival, but not overall survival, compared with Navelbine alone in the treatment of recurrent breast cancer. It is not clear whether sequential treatment (one type of chemotherapy followed by another versus administration of both at the same time) would be beneficial to these patients.

Thus, there is phase III evidence for this combination. I consider it no longer investigational and to my knowledge no clinical trials with it are currently ongoing.

Martin M, Ruiz A, Munoz M, et al. Gemcitabine plus vinorelbine versus vinorelbine monotherapy in patients with metastatic breast cancer previously treated with anthracyclines and taxanes: final results of the V. Heinemann et al, Treatment options for patients with pretreated metastatic breast cancer
The Lancet Oncology, Volume 8, Issue 3, Pages 187-189, 2007

Andrew D. Seidman The Evolving Role of Gemcitabine in the Management of Breast Cancer
Oncology Vol. 60, No. 3, 2001

Ermelinda De Maio at al, Vinorelbine plus 3-weekly trastuzumab in metastatic breast cancer: a single-centre phase 2 trial
BMC Cancer 2007, 7:50

nccn.org, breast cancer

Adjuvant TCH or AC-TH – pro

M Levin, MD — Tue, 04 Sep 2012 14:10:55 +0000

Recent evidence has put TCH on par with other standard adjuvant regimens. Previously two independent phase II studies have shown that this combination of carboplatin and docetaxel (Taxotere®; Aventis Pharmaceuticals, Inc.; Bridgewater, NJ) is active in the first-line treatment of metastatic breast cancer. Based on these promising results of combining trastuzumab with chemotherapy, nonanthracycline alternatives were investigated, with many of them incorporating platinum agents. The Breast Cancer International Research Group (BCIRG) conducted two pilot phase II trials of patients with advanced breast cancer overexpressing or with amplified HER2, in which trastuzumab was administered in combination with carboplatin/docetaxel or cisplatin/docetaxel.
The benefit of adding carboplatin to paclitaxel and trastuzumab in the first-line treatment of HER2-overexpressing metastatic breast cancer was further shown in results from an ongoing phase III study.

In the Herceptin Adjuvant (HERA) trial, the addition of one-year trastuzumab following (neo)adjuvant chemotherapy with AC was superior to observation after chemotherapy in terms of disease-free survival (DFS) (hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.43 to 0.67), recurrence-free survival (HR 0.50, 95% CI 0.40 to 0.63), and distant-disease-free survival (HR 0.40, 95% CI 0.40 to 0.66).
In a combined analysis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial and the North Central Cancer Treatment Group (NCCTG) N9831 trial, the addition of one-year trastuzumab concurrent with adjuvant paclitaxel following adjuvant doxorubicin and cyclophosphamide was superior to no trastuzumab in terms of disease-free survival (HR 0.48, p-value 3×10-12), time-to-first-distant-recurrence (TTR) (HR 0.47, p-value 8×10-10), and overall survival (OS) (HR 0.67, p-value 0.015).

In terms of using TCH regimen rather than AC+ paclitaxel/Herceptin, the NCCN does lsit it as an option, although it lists AC+T/Herceptin as the preferred option. There is a trial supporting its use, BCIRG 006. As with the other trials comparing chemotherapy alone vs chemotherapy plus trastuzumab, the addition of trastuzumab to AC T chemotherapy reduced the risk of disease recurrence by nearly 50% (hazard ratio 0.46, P < .01). The TCH triplet arm, which included trastuzumab, also led to better outcomes than chemotherapy alone (hazard ratio 0.61, P < .01). The comparison of the 2 trastuzumab-containing arms was underpowered, owing to the few events in each arm. However, as of the available follow-up, there is the suggestion that the risk of recurrence was lower in the AC TH arm than in the TCH arm.

An October 6, 2012 study in The New England Journal of Medicine included 3,222 women in three groups. One received Adriamycin (doxorubicin) and Cytoxan (cyclophosphamide) followed by Taxotere (docetaxel) (AC-T). One received AC-T plus 52 weeks of Herceptin (AC-T plus H). The last received Taxotere, Paraplatin (carbobplatin) and 52 weeks of Herceptin (TCH).

In terms of effectiveness, the AC-T plus H and TCH groups had similar disease-free and overall survival rates, and both were superior to the group that did not receive Herceptin.

In terms of side-effects, the AC-T plus H group experienced “significantly higher” rates of congestive heart failure and cardiac dysfunction than the TCH group. There were seven cases of leukemia in the AC-T plus H group and one in the TCH group.

The authors concluded that the addition of one year of Herceptin significantly improved disease-free and overall survival. The risk-benefit ratio favored the TCH combination over AC-T plus H, “given its similar efficacy, fewer acute toxic effects, and lower risks of cardiotoxicity and leukemia.” Subsequent editorial, leters and discussions in trhow away journals presented arguments for and against this conculsion.

Hayes DF. Steady progress against HER2-positive breast cancer.N Engl J Med. 2011 Oct 6;365(14):1336-8.

Comment on

N Engl J Med. 2011 Oct 6;365(14):1273-83.

Edith A. Perez Carboplatin in Combination Therapy for Metastatic Breast Cancer The Oncologist, Vol. 9, No. 5, 518-527, September 2004; Trudeau M, Madarnas Y, McCready D, Pritchard KI, Messersmith H, Breast Cancer Disease Site Group. The role of trastuzumab in adjuvant and neoadjuvant therapy in women with HER2/neu-overexpressing breast cancer: a clinical practice guideline. Toronto (ON): Cancer Care Ontario (CCO); 2006 May 12. 28 p. (Evidence-based series; no. 1-24). [58 references]

http://nccn.org/professionals/physician_gls/PDF/breast.pdf

Slamon D, Eiermann W, Robert N, et al. Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC–>T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC–>TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 positive early breast cancer patients: BCIRG 006 study. Breast Cancer Res Treat. 2005;94(suppl 1):S5. Abstract 1.