Cytotoxic and hormonal treatment for metastatic breast cancer: a systematic review of published randomized trials involving 31,510 women.

Fossati, Roldano; Confalonieri, C; Torri, Valter; Ghislandi, E; Penna, Antônio; Pistotti, Vanna; Tinazzi, Angelo; Liberati, Anna Marina

doi:10.1200/jco.1998.16.10.3439

Cited by 471 publications

(203 citation statements)

References 173 publications

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“…28 In the metastatic setting, anthracyclines have improved efficacy compared to nonanthracycline regimens and confer a survival benefit. 29 In hormone-resistant prostate cancer, which is generally associated with metastatic bone disease, epirubicin alone or in combination with other chemotherapy agents has a positive impact on symptom palliation, quality of life and survival. 30,31 Doxorubicin is a complex drug in terms of its cytotoxic mechanisms of action.…”

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confidence: 99%

Sequence‐ and schedule‐dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells

Neville-Webbe

Rostami‐Hodjegan

Evans

et al. 2004

Intl Journal of Cancer

146

104

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We investigated whether the combination of zoledronic acid and doxorubicin induced apoptosis of breast and prostate cancer cell lines, and if synergistic interaction was present. We investigated whether the levels of cell death altered depending on the sequence in which the drugs were administered and the possible mechanism of action responsible for the increased cell death following combined treatments. Breast and prostate cancer cells were treated with zoledronic acid alone, doxorubicin alone, or drugs in sequence (doxorubicin before, after, or with zoledronic acid), and the levels of apoptotic death were determined by evaluation of nuclear morphology. We found that clinically relevant concentrations of doxorubicin and zoledronic acid induced sequence-and schedule-dependent apoptosis of breast and prostate cancer cells. For maximal apoptosis, cells had to be pretreated for 24 hr with doxorubicin before immediate treatment with zoledronic acid for 1 hr. This observation is a characteristic feature of cell cycle phase-specific synergistic effect. Replacing zoledronic acid with the nonnitrogen-containing bisphosphonate clodronate did not induce increased apoptosis. Induction of apoptosis was mainly via inhibition of the mevalonate (MVA) pathway, as addition of the MVA pathway intermediary geranylgeraniol inhibited the induction of apoptosis by doxorubicin followed by zoledronic acid. In conclusion, combined treatment of breast and prostate cancer cell lines with clinically relevant doses of doxorubicin and zoledronic acid induces apoptosis in a synergistic fashion. These findings may have relevance for the clinical setting, particularly breast cancer patients receiving these drugs in the adjuvant setting.Key words: breast cancer; apoptosis; zoledronic acid; doxorubicin; synergistic interaction Zoledronic acid is a potent third-generation nitrogen-containing bisphosphonate and is the only bisphosphonate licensed to treat bone metastases from a variety of solid tumors and in multiple myeloma. In clinical practice, an increasing number of breast and prostate cancer patients are receiving zoledronic acid at earlier stages of their treatment in order to manage their metastatic bone disease.Zoledronic acid inhibits osteoclastic bone resorption, which occurs at an accelerated pace due to the presence of tumor cells in the bone microenvironment. 1 Nitrogen-containing bisphosphonates affect osteoclast action by inhibition of enzymes of the mevalonate pathway. 2 Target enzymes include farnesyl pyrophosphate synthase 3,4 and/or geranylgeranylpyrophosphate synthase, 5 leading to a lack of formation of farnesyl pyrophosphate and geranylgeranyl pyrophosphate. These isoprenoids are requisite for posttranslation lipid modification (i.e., farnesylation and geranylgeranylation) of signaling GTPases, such as Ras, Rho and Rac. 6 As these control a variety of important osteoclast cell functions, their loss ultimately leads to osteoclast apoptosis through caspase-3 enzyme activation. 7 In addition to their inhibitory effect on osteocl...

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confidence: 99%

Sequence‐ and schedule‐dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells

Neville-Webbe

Rostami‐Hodjegan

Evans

et al. 2004

Intl Journal of Cancer

146

104

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“…However, chemotherapy can also improve survival and may enhance quality of life (Fossati et al, 1998). The anthracyclines have long been considered to be the most active agents in MBC, with reported response rates of about 50% for monotherapy (Findlay and Walker-Dilks, 1998;Ormrod et al, 1999).…”

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confidence: 99%

“…Response rates of between 50 and 60% have been reported (Bonadonna et al, 1995). The addition of doxorubicin to combination regimens in MBC is associated with improved response rates (to between 60 and 80%) in advanced breast cancer (A'Hern et al, 1993;Fossati et al, 1998). However, no survival benefit has been demonstrated (Fossati et al, 1998).…”

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confidence: 99%

“…The addition of doxorubicin to combination regimens in MBC is associated with improved response rates (to between 60 and 80%) in advanced breast cancer (A'Hern et al, 1993;Fossati et al, 1998). However, no survival benefit has been demonstrated (Fossati et al, 1998). Commonly used first-line anthracycline-containing regimens involve the addition of either doxorubicin or epirubicin to fluorouracil and cyclophosphamide (FAC or FEC, respectively) (French Epirubicin Study Group, 1988;Italian Multicentre Breast Study with Epirubicin, 1988).…”

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confidence: 99%

“…However, improvements in tumour response rates achieved by combination therapies are frequently hampered by an increase in toxicity (Fossati et al, 1998). It has been suggested that toxicity can be reduced if different components of chemotherapeutic regimens are administered either alternately (Goldie et al, 1982) or sequentially (Day, 1986).…”

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Sequential or alternating administration of docetaxel (Taxotere®) combined with FEC in metastatic breast cancer: a randomised phase II trial

et al. 2002

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The aim of this study, using a Fleming single-stage design, was to explore the efficacy and safety of Taxotere 1 100 mg m 72 docetaxel and FEC 75 cyclophosphamide 500 mg m 72 , fluorouracil 500 mg m 72 and epirubicin 75 mg m 72 , in alternating and sequential schedules for the first-line treatment of metastatic breast cancer. One hundred and thirty-six women were randomly allocated, to one of three treatment regimens: DTX 100 plus FEC 75, alternated for eight courses (ALT); four courses of DTX 100 followed by four courses of FEC 75 (SEQ T); or four courses of FEC 75 followed by four courses of DTX 100 (SEQ F). One hundred and thirty-one women were evaluable for tumour response. Although the treatment outcome was equivalent in the two sequential arms and the alternating regimen (P=0.110, not significant), the response rate was less encouraging in the SEQ F arm (52.3%) than in the other two arms (71.1% for ALT and 70.5% for SEQ T), in which docetaxel was administered first. Time to progression was similar in the ALT, SEQ T and SEQ F arms (9.5, 9.3 and 10.4 months respectively). Grade 3 -4 neutropenia was observed in nearly all patients; febrile neutropenia occurred in 9% (ALT), 16% (SEQ T) and 2% (SEQ F) of patients. Few patients (49%) developed grade 3 -4 non-haematological toxicities. Relative dose intensity was 97 -99% for all regimens. All treatment regimens were active and well tolerated.

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Induction of thymidine phosphorylase expression and enhancement of efficacy of capecitabine or 5?-deoxy-5-fluorouridine by cyclophosphamide in mammary tumor models

et al. 1999

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Thymidine phosphorylase (dThdPase) is an essential enzyme for the activation of the oral cytostatic drugs capecitabine (N4‐pentyloxycarbonyl‐5′‐deoxy‐5‐fluorocytidine, Xeloda™) and its intermediate metabolite doxifluridine [5′‐deoxy‐5‐fluorouridine (5′‐dFUrd, Furtulon®)] to 5‐fluorouracil (5‐FUra) in tumors. In a previous study, we found that several cytostatics were able to up‐regulate tumor levels of dThdPase in a human colon cancer xenograft model. In the present study, we confirmed that the administration of cytostatics used for breast cancer treatment, such as taxanes and cyclophosphamide (CPA), up‐regulated the tumor level of dThdPase in mammary tumor models as well. Because the dThdPase up‐regulation was observed even when CPA was given orally, we investigated further the usefulness of combination therapy with the 2 oral drugs, 5′‐dFUrd/capecitabine and CPA in mammary tumor models. Daily oral administration of CPA up‐regulated human dThdPase levels in the tumor tissue of mice bearing a human mammary tumor xenograft, MX‐1, whereas in the small intestine and liver, it did not affect levels of pyrimidine nucleoside phosphorylases (PyNPase) including dThdPase and uridine phosphorylase. The preferential up‐regulation of PyNPase activity in the tumor by CPA administration was also confirmed in mice bearing a syngeneic murine mammary adenocarcinoma, A755. In both models, combination therapy of 5′‐dFUrd/capecitabine with CPA showed synergistic antitumor activity, without significant potentiation of toxicity. In contrast, treatment with CPA and either 5‐FUra or UFT (a mixture of tegafur and uracil) in combination showed only additive activity. Our results suggest that CPA and capecitabine/5′‐dFUrd, both available for oral administration, would be good partners, and that clinical trials with this drug combination against breast cancer are warranted. Int. J. Cancer 83:127–134, 1999. © 1999 Wiley‐Liss, Inc.

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Cytotoxic and hormonal treatment for metastatic breast cancer: a systematic review of published randomized trials involving 31,510 women.

Abstract: Despite some evidence of effectiveness of specific regimens, the relevance of these findings is limited by the modest survival benefit and the lack of evaluation of the quality-of-life impact of these treatments.

Cited by 471 publications

References 173 publications

Sequence‐ and schedule‐dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells

Sequence‐ and schedule‐dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells

Sequential or alternating administration of docetaxel (Taxotere®) combined with FEC in metastatic breast cancer: a randomised phase II trial

Induction of thymidine phosphorylase expression and enhancement of efficacy of capecitabine or 5?-deoxy-5-fluorouridine by cyclophosphamide in mammary tumor models

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