Zeba Aziz

Breast Cancer in Limited‐Resource Countries: Treatment and Allocation of Resources

Abstract:  Treating breast cancer under the constraints of significantly limited health care resources poses unique challenges that are not well addressed by existing guidelines. We present evidence‐based guidelines for systematically prioritizing cancer therapies across the entire spectrum of resource levels. After consideration of factors affecting the value of a given breast cancer therapy (contribution to overall survival, disease‐free survival, quality of life, and cost), we assigned each therapy to one of four incremental levels—basic, limited, enhanced, or maximal—that together map out a sequential and flexible approach for planning, establishing, and expanding breast cancer treatment services. For stage I disease, basic‐level therapies are modified radical mastectomy and endocrine therapy with ovarian ablation or tamoxifen; therapies added at the limited level are breast‐conserving therapy, radiation therapy, and standard‐efficacy chemotherapy (cyclophosphamide, methotrexate, and 5‐fluorouracil [CMF], or doxorubicin and cyclophosphamide [AC], epirubicin and cyclophosphamide [EC], or 5‐fluorouracil, doxorubicin, and cyclophosphamide [FAC]); at the enhanced level, taxane chemotherapy and endocrine therapy with aromatase inhibitors or luteinizing hormone–releasing hormone (LH‐RH) agonists; and at the maximal level, reconstructive surgery, dose‐dense chemotherapy, and growth factors. For stage II disease, the therapy allocation is the same, with the exception that standard‐efficacy chemotherapy is a basic‐level therapy. For locally advanced breast cancer, basic‐level therapies are modified radical mastectomy, neoadjuvant chemotherapy (CMF, AC, or FAC), and endocrine therapy with ovarian ablation or tamoxifen; the therapy added at the limited level is postmastectomy radiation therapy; at the enhanced level, breast‐conserving therapy, breast‐conserving whole‐breast radiation therapy, taxane chemotherapy, and endocrine therapy with aromatase inhibitors or LH‐RH agonists; and at the maximal level, reconstructive surgery and dose‐dense chemotherapy and growth factors. For metastatic or recurrent disease, basic‐level therapies are total mastectomy for ipsilateral in‐breast recurrence, endocrine therapy with ovarian ablation or tamoxifen, and analgesics; therapies added at the limited level are radiation therapy and CMF or anthracycline chemotherapy; at the enhanced level, chemotherapy with taxanes, capecitabine, or trastuzumab, endocrine therapy with aromatase inhibitors, and bisphosphonates; and at the maximal level, chemotherapy with vinorelbine, gemcitabine, or carboplatin, growth factors, and endocrine therapy with fulvestrant. Compared with the treatment of early breast cancer, the treatment of advanced breast cancer is more resource intensive and generally has poorer outcomes, highlighting the potential benefit of earlier detection and diagnosis, both in terms of conserving scarce resources and in terms of reducing morbidity and mortality. Use of the scheme outlined here should help ministers of health, policymakers, administrators, and institutions in limited‐resource settings plan, establish, and gradually expand breast cancer treatment services for their populations.

Efficacy and safety of casopitant mesylate, a neurokinin 1 (NK1)-receptor antagonist, in prevention of chemotherapy-induced nausea and vomiting in patients receiving cisplatin-based highly emetogenic chemotherapy: a randomised, double-blind, placebo-controlled trial

BACKGROUND Chemotherapy-induced nausea and vomiting (CINV) remains a clinical management problem after treatment with highly emetogenic chemotherapy (HEC). We therefore designed and carried out a multicentre, randomised, double-blind, placebo-controlled trial to assess whether a three-drug antiemetic regimen of ondansetron, dexamethasone, and the neurokinin-1-receptor antagonist casopitant mesylate was able to prevent acute and delayed CINV events in patients naive to chemotherapy with a malignant solid tumour who were scheduled to receive cisplatin-based HEC regimens. METHODS The study was done between Nov 6, 2006, and Oct 9, 2007, in 77 participating centres in 22 countries. All 810 patients enrolled in the trial received dexamethasone and ondansetron. Patients were randomly assigned to also receive placebo (n=269), single oral dose of casopitant mesylate (150 mg oral, n=271), or 3-day intravenous plus oral casopitant mesylate (90 mg intravenous on day 1 plus 50 mg oral on days 2 and 3, n=270). Randomisation was done using a central telephone system at the study level, because some centres were expected to recruit only a few patients during the study period. The primary endpoint was the proportion of patients achieving complete response (no vomiting, retching, or use of rescue medications) in the first 120 h after receiving HEC. Efficacy analysis was done on the modified intention-to-treat population (n=800), which included all patients who received placebo or study drug and HEC (n=265 control, n=266 single-dose oral casopitant mesylate, n=269 3-day intravenous and oral casopitant mesylate). Safety was reported in 802 patients who received either placebo or study medication. This study is registered with ClinicalTrials.gov, NCT00431236. FINDINGS Significantly more patients in each casopitant group achieved complete response in cycle 1 of HEC treatment than did those in the control group (175 [66%] patients in the control group, 228 [86%] in the single-dose oral casopitant mesylate group [p<0.0001 vs control], and 214 [80%] in the 3-day intravenous plus oral casopitant mesylate group (p=0.0004 vs control]). This improvement was sustained over multiple cycles of HEC. Adverse events occurred in 205 (77%) patients in the single-dose oral casopitant mesylate group and 203 (75%) patients in the 3-day intravenous and oral casopitant mesylate group compared with 194 (73%) of patients in the control group. The most common serious adverse events were neutropenia (n=5 [3%] in the control group, n=3 [1%] in the single-dose oral casopitant mesylate group, and n=11 [4%] in the 3-day intravenous plus oral casopitant mesylate group), febrile neutropenia (n=1 [<1%] in the control group, n=4 [1%] in the single-dose oral casopitant mesylate group, and n=6 [2%] in the 3-day intravenous plus oral casopitant mesylate group), and dehydration (n=4 [2%] in the control group, n=2 [<1%] in the single-dose oral casopitant mesylate group, and n=1 [<1%] in the 3-day intravenous plus oral casopitant mesylate group). INTERPRETATION A three-drug regimen including a single oral dose or 3-day intravenous plus oral regimen of casopitant mesylate plus dexamethasone and ondansetron significantly reduced CINV events in patients receiving HEC compared with a two-drug regimen of dexamethasone and ondansetron. FUNDING GlaxoSmithKline.

Phase III Trial of Casopitant, a Novel Neurokinin-1 Receptor Antagonist, for the Prevention of Nausea and Vomiting in Patients Receiving Moderately Emetogenic Chemotherapy

PURPOSE The purpose of this phase III trial was to evaluate the efficacy and safety of regimens containing casopitant, a novel neurokinin-1 receptor antagonist, for the prevention of chemotherapy-induced nausea and vomiting during the first cycle in patients receiving moderately emetogenic chemotherapy (MEC). PATIENTS AND METHODS Predominantly female patients (98%) diagnosed with breast cancer (96%) who were chemotherapy-naïve and scheduled to receive an anthracycline and cyclophosphamide (AC) -based regimen were enrolled onto this multinational, randomized, double-blind, parallel-group, placebo-controlled clinical trial. All patients received dexamethasone 8 mg intravenously (IV) on day 1 and oral ondansetron 8 mg twice daily on days 1 to 3. Patients were randomly assigned to a control arm (placebo), a single oral dose casopitant arm (150 mg orally [PO] on day 1), a 3-day oral casopitant arm (150 mg PO on day 1 plus 50 mg PO on days 2 to 3), or a 3-day IV/oral casopitant arm (90 mg IV on day 1 plus 50 mg PO on days 2 to 3). The primary end point was the proportion of patients achieving complete response (no vomiting/retching or rescue medications) in the first 120 hours after the initiation of MEC. RESULTS A significantly greater proportion of patients in the single-dose oral casopitant arm, 3-day oral casopitant arm, and 3-day IV/oral casopitant arm achieved complete response (73%, 73%, and 74%, respectively) versus control (59%; P < .0001). The study did not demonstrate a reduced proportion of patients with nausea or significant nausea in those receiving casopitant. Adverse events were balanced among study arms. CONCLUSION All casopitant regimens studied were more effective than the control regimen. Casopitant was generally well tolerated.

Frequency of the CHEK2 1100delC Mutation among Women with Breast Cancer: An International Study

A founder allele in the CHEK2 gene (1100delC) has been associated with an elevated risk of breast cancer. This allele is responsible for the majority of CHEK2-associated breast cancers in women from northern European countries; however, within Europe, it seems to be rare in countries that are close to the Mediterranean. The frequency of the 1100delC allele has not been measured in non-White populations. We measured the frequency of the CHEK2 founder allele in 3,882 breast cancer patients and 8,609 controls from various countries. The allele was not seen among Asian patients (from Pakistan or the Philippines) and was present in 1 of 155 cases from Brazil. Among White women, the allele was present in 1.5% of 825 familial cases of breast cancer and in 0.7% of 1,106 patients with nonfamilial breast cancer. The allele was equally frequent in Jewish and non-Jewish patients. We estimate that the CHEK2 1100delC allele is associated with an odds ratio of 2.6 for breast cancer, which corresponds to a lifetime risk of approximately 24% in Ontario.

Locally advanced breast cancer: treatment guideline implementation with particular attention to low- and middle-income countries.

The management of locally advanced breast cancer (LABC) is guided by scientific advances but is limited by local resources and expertise. LABC remains very common in low‐resource countries. The Systemic Therapy Focus Group met as part of the Breast Health Global Initiative (BHGI) Summit in Budapest, Hungary, in October 2007 to discuss management and implementation of primary systemic therapy (PST) for LABC. PST is standard treatment for large operable breast cancer in enhanced‐resource settings and, in all resource settings, should be standard treatment for inoperable breast cancer and for LABC. Standard PST includes anthracycline‐based chemotherapy. The addition of sequential taxanes after anthracycline improves pathologic responses and breast‐conservation rates and is appropriate at enhanced‐resource levels; however, costs and lack of clear survival benefit do not justify their use at limited‐resource levels. It remains to define better the role of endocrine therapy as PST, but it is acceptable in elderly women. Aromatase inhibitors have produced better results than tamoxifen in postmenopausal patients and are used in enhanced‐resource settings. The less expensive tamoxifen remains useful in low‐resource countries. Trastuzumab combined with chemotherapy yields high pathologic response rates in patients with HER2/neu‐overexpressing tumors; its use in low‐resource countries is limited by high costs. Most studies on PST of LABC were conducted in countries with enhanced resources. BHGI encourages conducting clinical trials in countries with limited resources. Cancer 2008;113(8 suppl):2315–24.

Treatment of chronic myeloid leukemia in the imatinib era : Perspective from a developing country

There is paucity of data from developing countries on the efficacy and safety of imatinib mesylate in chronic myeloid leukemia (CML). The primary objective of this study was to document complete and partial cytogenetic responses to imatinib in all phases of CML. Secondary objectives included evaluations of complete hematologic response, safety, time to progression, and survival.

The prevalence of germ-line TP53 mutations in women diagnosed with breast cancer before age 30

Germ-line mutations in the TP53 gene are rare, but predispose women to a range of cancer types, including early-onset breast cancer. Breast cancers in women from families with the Li-Fraumeni syndrome often occur before age 30. The prevalence of deleterious TP53 mutations in unselected women with early-onset breast cancer is not precisely known. If mutations were found to be sufficiently common, it might be prudent to offer genetic testing to affected women in this age group. We screened the entire TP53 gene in the germ-line DNA from 95 women of various ethnic groups who were diagnosed with breast cancer before age 30, and who had previously been found to be negative for BRCA1 and BRCA2 mutations. No TP53 mutation was found. This study does not support a policy that TP53 testing should be offered routinely to unselected women with early-onset breast cancer in the absence of a family history of cancer.

Assessment of quality of life with imatinib mesylate as first-line treatment in chronic phase-chronic myeloid leukemia

Imatinib mesylate (IM) is a first-line treatment of chronic phase-chronic myeloid leukemia (CP-CML). The primary objective of this study was to assess the quality of life (QOL) in patients with CP-CML treated with IM. Ninety patients with newly diagnosed CP-CML were assessed for QOL with first-line IM. Patients completed the cancer-specific FACT-BRM questionnaire (functional assessment of cancer therapy-biologic response modifiers) at baseline and at 3 and 6 months. FACT-BRM consists of subscales including physical well-being (PWB), social and family well-being (SFWB), emotional well-being (EWB), functional well-being (FWB), BRM-physical, and BRM-mental. The primary endpoint was the Trial Outcome Index (TOI), created as a measure of physical function and well-being. An increase of ≥5 from baseline was considered to be a clinically significant improvement. The mean TOI score increased from 75.5 at baseline to 85.2 (p<0.0001) at 6 months, representing a healthy QOL. When comparing the individual TOI subscales, there was a mean increase of 16.4 in the daily functioning and well-being score, and a mean decrease of 6.2, 4.9, and 16.1 was noted in fatigue, emotional/cognitive dysfunction, and side-effects scores at 6 months, respectively. Improvement was not affected by age, sex, or Sokal score. With prolonged treatment, IM results in a higher physical well-being, less fatigue and emotional and cognitive dysfunction, and very few side-effects.

Effect of Social Class Disparities on Disease Stage, Quality of Treatment and Survival Outcomes in Breast Cancer Patients from Developing Countries

Abstract:  To assess the relationship between social class disparities on disease stage on presentation, quality of treatment, and survival outcome of breast cancer patients in Pakistan and compare our data with SEER (Surveillance, Epidemiology, and End Results) data from US on white and African‐American women to evaluate differences in disease stage and survival outcomes. Patients were evaluated for age, tumor size, grade, receptor status, stage, and 5‐year survival and were compared with SEER data. Socio‐economic status was evaluated with financial income. Patients were divided in poor and middle/high groups. Excellent and comparable 5‐year survival with SEER data was observed with localized disease in all groups from different strata. Advanced disease was more common in the disadvantaged group with negligible 5‐year survivals. Development and implementation of early detection programs, public awareness, and clinical and breast self examination that are more pragmatic in the settings of countries with limited resources are essential.

Quality-of-life and quality-adjusted survival (Q-TWiST) in patients receiving lapatinib in combination with paclitaxel as first-line treatment for metastatic breast cancer

Abstract Background: In a phase 3 randomized, multicenter, double-blind, placebo-controlled study, first-line therapy with lapatinib plus paclitaxel significantly improved clinical outcomes based on a pre-planned analysis of ErbB2+ metastatic breast cancer patients (GSK Study #EGF30001; ClinicalTrials.gov identifier: NCT00075270). Patients with ErbB2− or untested did not significantly benefit. This article focuses on the quality of life (QOL) and quality-adjusted survival outcomes (Q-TWiST) in the study. Methods: QOL was assessed using the Functional Assessment of Cancer Therapy–Breast (FACT-B). Changes from baseline were analyzed using ANCOVAs, repeated measures and pattern mixture modeling. The Q-TWiST method was used to examine the trade-off between toxicities and delayed progression. Trial registration: ClinicalTrials.gov identifier: NCT00075270. Results: The study included 579 subjects, of whom 86 were ErbB2+. In the ITT population, no significant differences in QOL or Q-TWiST scores were observed. In the ErbB2+ subgroup, the lapatinib plus paclitaxel (L + P) arm demonstrated stable FACT-B scores over the first year, while average scores for patients on P + placebo (P + pla) monotherapy decreased (change from baseline: L + P, p = 0.99; P + pla, p = 0.01). Clinically meaningful differences were observed between treatment arms on the FACT-B, Trial Outcome Index and breast cancer subscale scores. Pattern mixture models suggested more QOL differentiation between treatments among patients who progressed or withdrew early. Q-TWiST differences between the arms in the ErbB2+ subgroup ranged from 2 to 15 weeks with an L + P advantage across all utility weight combinations. Conclusions: In the ITT population, results provide no evidence of QOL differences between treatment groups. In a small, prospectively-defined subgroup of ErbB2+ patients, L + P resulted in more stable QOL and more quality-adjusted survival than paclitaxel monotherapy, representing clinically important differences between treatments.