Vinod Raina

Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial

Summary Background For women with oestrogen receptor (ER)-positive early breast cancer, treatment with tamoxifen for 5 years substantially reduces the breast cancer mortality rate throughout the first 15 years after diagnosis. We aimed to assess the further effects of continuing tamoxifen to 10 years instead of stopping at 5 years. Methods In the worldwide Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial, 12 894 women with early breast cancer who had completed 5 years of treatment with tamoxifen were randomly allocated to continue tamoxifen to 10 years or stop at 5 years (open control). Allocation (1:1) was by central computer, using minimisation. After entry (between 1996 and 2005), yearly follow-up forms recorded any recurrence, second cancer, hospital admission, or death. We report effects on breast cancer outcomes among the 6846 women with ER-positive disease, and side-effects among all women (with positive, negative, or unknown ER status). Long-term follow-up still continues. This study is registered, number ISRCTN19652633. Findings Among women with ER-positive disease, allocation to continue tamoxifen reduced the risk of breast cancer recurrence (617 recurrences in 3428 women allocated to continue vs 711 in 3418 controls, p=0·002), reduced breast cancer mortality (331 deaths vs 397 deaths, p=0·01), and reduced overall mortality (639 deaths vs 722 deaths, p=0·01). The reductions in adverse breast cancer outcomes appeared to be less extreme before than after year 10 (recurrence rate ratio [RR] 0·90 [95% CI 0·79–1·02] during years 5–9 and 0·75 [0·62–0·90] in later years; breast cancer mortality RR 0·97 [0·79–1·18] during years 5–9 and 0·71 [0·58–0·88] in later years). The cumulative risk of recurrence during years 5–14 was 21·4% for women allocated to continue versus 25·1% for controls; breast cancer mortality during years 5–14 was 12·2% for women allocated to continue versus 15·0% for controls (absolute mortality reduction 2·8%). Treatment allocation seemed to have no effect on breast cancer outcome among 1248 women with ER-negative disease, and an intermediate effect among 4800 women with unknown ER status. Among all 12 894 women, mortality without recurrence from causes other than breast cancer was little affected (691 deaths without recurrence in 6454 women allocated to continue versus 679 deaths in 6440 controls; RR 0·99 [0·89–1·10]; p=0·84). For the incidence (hospitalisation or death) rates of specific diseases, RRs were as follows: pulmonary embolus 1·87 (95% CI 1·13–3·07, p=0·01 [including 0·2% mortality in both treatment groups]), stroke 1·06 (0·83–1·36), ischaemic heart disease 0·76 (0·60–0·95, p=0·02), and endometrial cancer 1·74 (1·30–2·34, p=0·0002). The cumulative risk of endometrial cancer during years 5–14 was 3·1% (mortality 0·4%) for women allocated to continue versus 1·6% (mortality 0·2%) for controls (absolute mortality increase 0·2%). Interpretation For women with ER-positive disease, continuing tamoxifen to 10 years rather than stopping at 5 years produces a further reduction in recurrence and mortality, particularly after year 10. These results, taken together with results from previous trials of 5 years of tamoxifen treatment versus none, suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis. Funding Cancer Research UK, UK Medical Research Council, AstraZeneca UK, US Army, EU-Biomed.

Lipid peroxidation, free radical production and antioxidant status in breast cancer

Reactive oxygen metabolites (ROMs), including superoxide anion (O2·−), hydrogen peroxide (H2O2) and hydroxyl radical (·OH), play an important role in carcinogenesis. There are some primary antioxidants such as superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) which protect against cellular and molecular damage caused by the ROMs. We conducted the present study to determine the rate of O2·− and H2O2 production, and concentration of malondialdehyde (MDA), as an index of lipid peroxidation, along with the SOD, GPx and CAT activities in 54 breast cancer (BC) patients. Forty-two age- and sex-matched patients with minor surgical problems, who had no history of any neoplastic or breast disorders, were taken as controls.The rate of O2·− production was significantly higher (p<0.001) in BC patients than controls, irrespective of clinical stages and menopausal status. Similarly, H2O2 production was significantly higher in BC patients, especially in stage III and postmenopausal groups, as compared to the respective controls. MDA concentration was also observed significantly elevated in stage II (p<0.001), stage III (p<0.01), postmenopausal (p<0.005), and premenopausal (p<0.02) group as compared to their corresponding controls. SOD and GPx activities were found significantly raised in all the groups (p<0.001), except the GPx activity was found a smaller alteration in stage IV (p<0.02). On the contrary, CAT activity was found significantly depressed in all the study groups. The maximum depression was observed in stage II (−61.8%). Lower CAT activity in our study may be the effect of higher production of ROMs, particularly O2·− and ·OH. SOD and GPx, however, were less effected by these higher ROMs production. The results of our study have shown a higher ROMs production and decreased CAT activity, which support the oxidative stress hypothesis in carcinogenesis. The relatively higher SOD and GPx may be due to the response of increased ROMs production in the blood. However, the higher SOD and GPx activities may be inadequate to detoxify high levels of H2O2 into H2O leading to the formation of the most dangerous ·OH radical followed by MDA. Therefore, administration of CAT may be helpful in the management of BC patients. However, further elaborate clinical studies are required to evaluate the role of such antioxidant enzymes in BC management.

Best Supportive Care Compared With Chemotherapy for Unresectable Gall Bladder Cancer: A Randomized Controlled Study

PURPOSE We designed this study to evaluate efficacy of modified gemcitabine and oxaliplatin (mGEMOX) over best supportive care (BSC) or fluorouracil (FU) and folinic acid (FA) in unresectable gall bladder cancer (GBC). PATIENTS AND METHODS Patients with unresectable GBC were enrolled for single center randomized study. Arm A, BSC; arm B, FU 425 mg/m(2) and FA 20 mg/m(2) intravenous (IV) bolus weekly for 30 weeks (FUFA); arm C, gemcitabine 900 mg/m(2) and oxaliplatin 80 mg/m(2) IV infusion on days 1 and 8 every 3 weeks for maximum of six cycles. Eighty-one patients were randomly assigned, arms A (n = 27), B (n = 28), and C (n = 26). RESULTS Complete response plus partial response in the three groups was 0 (0%), four (14.3%), and eight (30.8%) respectively (P < .001). Two patients in the mGEMOX arm and one patient in the FUFA arm underwent curative resection after chemotherapy. One patient in the mGEMOX arm had complete pathologic response. Median overall survival (OS) was 4.5, 4.6, and 9.5 months for the BSC, FUFA, and mGEMOX arms (P = .039), respectively. Progression-free survival (PFS) was 2.8, 3.5, and 8.5 months for the three groups (P < .001). There was no difference in grade 3/4 toxicities in the chemotherapy arms except transaminitis, which was more prevalent in mGEMOX arm (P = .04). Two patients in the FUFA arm and 10 patients in the mGEMOX arm had grade 3 or 4 myelosuppression. Two patients in the mGEMOX group had neutropenic fever that resolved with antibiotics. CONCLUSION This randomized controlled trial confirmed the efficacy of chemotherapy (mGEMOX) compared with BSC and FUFA in improving OS and PFS in unresectable GBC.

A double-blind, randomised, placebo-controlled, phase 2b study evaluating sorafenib in combination with paclitaxel as a first-line therapy in patients with HER2-negative advanced breast cancer.

BACKGROUND We conducted a phase 2b, randomised, double-blind, placebo-controlled screening trial to evaluate the addition of the multikinase inhibitor sorafenib (antiproliferative/antiangiogenic) to first-line paclitaxel for human epidermal growth factor receptor 2 (HER2)-negative locally recurrent/metastatic breast cancer. METHODS Patients were randomised to paclitaxel (90mg/m(2), weekly, intravenously, 3 weeks on/1 week off) plus sorafenib (400mg, orally, twice daily) or placebo. The primary endpoint was progression-free survival (PFS). A sample size of 220 patients was planned with relative risk ≤ 0.82 (1-sided α=0.14) after 120 events supporting a treatment effect. FINDINGS Patients were randomised in India (n=170), the United States (n=52) and Brazil (n=15). Median PFS was 6.9 months for sorafenib versus 5.6 months for placebo (hazard ratio (HR)=0.788; 95% confidence interval (CI), 0.558-1.112; P=0.1715 [1-sided P=0.0857]). The addition of sorafenib increased time to progression (median, 8.1 versus 5.6 months; HR=0.674; 95% CI 0.465-0.975; P=0.0343) and improved overall response (67% versus 54%; P=0.0468). Overall survival did not statistically differ (median, 16.8 versus 17.4 months; HR=1.022; 95% CI 0.715-1.461; P=0.904). Grade 3/4 toxicities (sorafenib versus placebo) included hand-foot skin reaction (31% versus 3%), neutropenia (13% versus 7%) and anaemia (11% versus 6%). Two treatment-related deaths occurred (malaria and liver dysfunction) in the sorafenib arm. INTERPRETATION The addition of sorafenib to paclitaxel improved disease control but did not significantly improve PFS to support a phase 3 trial of similar design. Toxicity of the combination was manageable with dose reductions.

Clinical features and prognostic factors of early breast cancer at a major cancer center in North India

BACKGROUND Data on the clinical profile of early breast cancer (EBC) from India is scant. Due to differences in genetics, environment, lifestyle, socio-demographic structure and ethnicity, the presentation and behavior of breast cancer in India may be different. AIMS To analyze the clinical presentation and outcome of EBC patients. SETTINGS AND DESIGN A single center retrospective study. MATERIALS AND METHODS Data from 487 EBC patients registered and treated at our institute from 1993 through 1999 were analyzed. Coxs multivariate regression test was used to determine prognostic factors for overall and disease-free survival (OS & DFS). RESULTS The median age was 47 years and 49.7% patients were pre-menopausal. Ninety-six per cent patients presented with a lump. Stages I, IIa, and IIb comprised 7.8%, 38.8%, and 47.6% respectively. Only 11.3% patients opted for breast-conserving surgery (BCS) while the remaining 88.7% underwent modified radical mastectomy (MRM). Adjuvant chemotherapy was administered to 275 (56.5%), and radiotherapy to 146 (29.9%). Estrogen receptor status was known in 173, of whom 93 (53.7%) were positive. Most patients were prescribed Tamoxifen for 5 years. At a median follow-up of 48 months, 126 (25.9%) patients had relapsed (systemic 107, loco-regional 19) and 94 (19.3%) had died. Five-year DFS and OS were 73% and 78%, respectively. On multivariate analysis, four positive nodes adversely influenced survival (P< 0.01). CONCLUSIONS The median age at presentation was 47 years, significantly lower than most Western figures. The majority (86.4%) had a lump size > two cm. BCS was done in only 11% and the rest underwent MRM. Nodal involvement was the significant prognostic factor.

Epidemiology, screening and diagnosis of breast cancer in the Asia–Pacific region: Current perspectives and important considerations

Because the Asia–Pacific region contains approximately 25% of the worlds population, the rapidly rising incidence of breast cancer in this area represents a serious global health problem. Epidemiologic and biologic profiles of breast cancer in the Asia–Pacific region differ from those in Western countries. Compared with the West, breast cancer occurs more frequently among young premenopausal women and women in urban areas. Breast cancer is also more frequently diagnosed in advanced stages than in Western countries, and tumors are more likely to be estrogen receptor‐ and progesterone receptor‐negative. These differences can impact treatment selection, response to treatment, and outcomes, including morbidity and mortality. Breast cancer mortality in some countries of the Asia–Pacific region is two‐fold higher than in Western countries. The screening, diagnosis, and management of patients with breast cancer in the Asia–Pacific region are associated with a number of unique challenges. These include patient misperceptions about the disease and its treatment, a lack of access to imaging equipment and diagnostic testing, inconsistencies in the implementation of breast cancer screening programs and limited access to expensive treatments. Whereas some of the more Westernized countries within this region have established screening programs, many areas are still lacking in adequate breast cancer screening facilities. Various cultural and economic barriers must be addressed to improve treatment and outcomes for Asian‐Pacific patients with breast cancer.

A Double-Blind, Randomized, Placebo-Controlled, Phase 2b Study Evaluating the Efficacy and Safety of Sorafenib (SOR) in Combination with Paclitaxel (PAC) as a First-Line Therapy in Patients (pts) with Locally Recurrent or Metastatic Breast Cancer (BC).

Introduction: SOR is a targeted therapeutic agent indicated for advanced renal cell carcinoma and hepatocellular carcinoma. SOR targets multiple kinases involved in tumor growth and angiogenesis. The TIES (Trials to Investigate the Effects of Sorafenib in BC) program includes 4 phase 2b randomized, double-blind, placebo-controlled screening trials in HER2-negative BC. Recently, the first of these trials, SOR+capecitabine (CAP) vs placebo (PL)+CAP demonstrated a significant progression-free survival (PFS) benefit in pts with advanced BC. Here we present initial results from the second of the 4 trials. This study evaluated the efficacy and safety of SOR in combination with PAC as a first-line regimen for pts with advanced BC.Methods: Pts with HER2-negative, locally recurrent or metastatic BC were eligible for first-line treatment for advanced BC. Previous cytotoxic (non-metastatic), endocrine, or radiation therapy was allowed. Pts were randomized 1:1 (stratified by visceral vs non-visceral metastatic disease) to SOR (400 mg, orally, twice daily, continuously) or PL in combination with PAC (90 mg/m2 weekly, IV, 3 weeks on/1 week off). The primary endpoint was PFS. Secondary endpoints included overall survival (OS), time to progression (TTP), overall response rate (ORR), and safety. A sample size of 220 pts was planned to detect a targeted HR of 0.65 (90% power and 1-sided a=0.14). The study is registered at ClinicalTrials.gov (NCT00499525).Results: From January 2008 to January 2009, 237 pts were randomized to SOR+PAC (n=119) vs PL+PAC (n=118), with 170 pts in India (74% vs 69%), 52 pts in the United States (21% vs 23%), and 15 pts in Brazil (5% vs 8%). Treatment groups were balanced for age (mean, 51.9 y), ECOG performance 0 (45%) and 1 (53%), stage IV disease (85%), visceral metastatic disease (75%), and previous non-metastatic chemo (58%). Results of the study were as follows for SOR+PAC vs PL+PAC: median PFS 6.9 vs 5.6 mos (HR 0.788; 95% CI, 0.558-1.112; 1-sided log rank P=0.0857), median TTP 8.1 vs 5.6 mo (HR 0.674; 95% CI, 0.465-0.975; 1-sided log rank P=0.0171), and ORR of 67% vs 54% (1-sided Cochran-Mantel-Haenszel P=0.0234). OS data are pending. Discontinuation of study treatment due to adverse events occurred in 23 pts (19%) in the SOR+PAC vs 5 pts (4%) in the PL+PAC. Grade 3/4 toxicities (SOR+PAC vs PL+PAC) included hand-foot skin reaction (30% vs 3%), asthenia (7% vs 3%), peripheral neuropathy (6% vs 7%), neutropenia (13% vs 7%), and anemia (11% vs 6%). Treatment-related deaths occurred in 2 pts (malaria and liver dysfunction), both in the SOR+PAC arm.Conclusions: Results of the primary endpoint, PFS, demonstrated a trend favoring SOR+PAC over PL+PAC in the treatment of advanced BC (HR 0.788; P=0.0857). In addition, significant improvements in TTP and ORR were observed. OS data are pending. There were no new toxicities observed with the combination and AEs were manageable. These data indicate that SOR provides added benefit when combined with PAC compared with single-agent PAC in the first-line treatment of advanced BC. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 44.

Does chemotherapy improve survival in gall bladder cancer

4202 Background: Carcinoma of gall bladder is 4th commonest cancer in females in Northern India. Incidence is 5.5/1,00,000 women. Surgery is only modality for cure. Majority of patients present in advanced inoperable stage where median survival is between 3-6 months and treatment options are analgesics, biliary stents, or palliative chemotherapy. Oxaliplatin, has demonstrated some activity in advanced adenocarcinoma of gall bladder (Proc Am Soc Clin Oncol 2002:21; 142b). To assess the impact of chemotherapy (5 FU, FA with or without Oxalipaltin) on survival this study was undertaken. MATERIAL AND METHODS 109 gall bladder cancer patients were seen from November 2000 to September 2003. Median age was 50 years, 72 were females (males to females ratio 1:2). Pain was the commonest presenting symptom seen in 96 ( 88%) patients, 55 ( 51%) patients had gall bladder stones, and 80 ( 72%) patients had metastaic disease. TREATMENT 50 patients received only analgesics, simple cholecystectomy was done in 16, radical cholecystectomy in 15, and 13 patients received adjuvant radiotherapy without or with (9 patients) FUFA. Oxaliplatin based palliative chemotherapy (FOLFOX or Oxaliplatin FUFA as reported earlier ASCO 2002:21; 142b or Oxaliplatin and Capecitabine) were used in 21 patients, and 5 patients received FUFA. RESULTS Median survival for whole group was 5 months ( range 0-34 months). Any form of anti cancer treatment improved survival. Median survival for patients who received no treatment versus palliative chemotherapy versus surgery followed by adjuvant treatment was 3, 5, and 10 months respectively ( p=0.0000). Median survival for patients who received any form of chemotherapy versus no chemotherapy was 10 versus 4 months ( p=0.03). Overall responses in Oxaliplatin based group were 24% including 1 CR ( another 20% had disease stabilization). Median survival was 10 months in patients who received FOLFOX. CONCLUSIONS This study reveals that patients receiving chemotherapy adjuvant or palliative had superior survival compared to others. Oxaliplatin based chemotherapy FOLFOX in particular may be superior to others as palliative chemotherapy. However, this must be tested in randomized controlled trial. No significant financial relationships to disclose.

Primitive Neuroectodermal Kidney Tumor: 2 Case Reports and Review of the Literature

Peripheral neuroectodermal tumors are uncommon cancers arising from outside the central nervous system. The urinary system is rarely involved. The differentiation of these tumors from other small cell cancer and neuroblastoma is based on immunohistochemical differences. We report 2 cases of such tumors arising from the renal parenchyma. Tumor behavior and treatment modalities are discussed.

Metronomics as maintenance treatment in oncology: time for chemo-switch.

The “cell kill” paradigm associated with maximum-tolerated dose (MTD) chemotherapy has shown remarkable success in many hematological malignancies, but unfortunately has failed to demonstrate sustained responses in majority of common advanced solid tumors. This failure can be attributable to heterogeneity of cancer cells within the tumor in terms of the rate of cell proliferation, genetic makeup, and micro-environmental selection giving rise to development of treatment resistance. In this context, Gatenby’s hypothesis of controlling tumor growth rather than eradicating it and treating it like a chronic disease may be more meaningful (1). The use of metronomic regimens alone or in combination with other new targeted therapies after MTD chemotherapy as maintenance treatment for longer period may pave the way for long-term cost-effective treatment.