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Old 11-20-2009, 11:40 AM   #1
Rich66
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Join Date: Feb 2008
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Chemo Combinations/sequences with oomph

Ann Oncol. 2009 Nov 25. [Epub ahead of print]
Gemcitabine and capecitabine in previously anthracycline-treated metastatic breast cancer: a multicenter phase II study (SOLTI 0301 trial).

Ciruelos EM, Cortés J, Cortés-Funes H, Mayordomo JI, Bermejo B, Ojeda B, Garc*a E, Rodr*guez CA, Muñoz M, Gómez P, Manso L, Andrés R, Lluch A, Saura C, Mendiola C, Baselga J.
Medical Oncology Department, University Hospital 12 de Octubre, Madrid.
BACKGROUND: On the basis of clinical activity of capecitabine and gemcitabine for metastatic breast cancer, we carried out a multicenter phase II clinical trial on the combination of these two agents in advanced anthracycline-pretreated breast cancer patients. Main objectives were to assess its efficacy and safety profile. PATIENTS AND METHODS: Seventy-six anthracycline-pretreated breast cancer patients were evaluated and were stratified according to previous treatment of advanced disease (group-1: not previously treated and group-2: previously treated). Study treatment consisted of gemcitabine 1000 mg/m(2), i.v., as 30 min-infusion, days 1 and 8 every 21 days, plus oral capecitabine 830 mg/m(2) b.i.d., days 1-14 every 21 days. RESULTS: Overall response rate was 61% for group-1, 48.5% for group-2 and 55.2% for the whole population. Clinical benefit rate was 73% for group-1, 80% for patients in group-2 and 76% for all patients. Median time to progression was 13.0 months for group-1, 8.2 months for group-2 and 11.1 months for the whole population. Most frequent grade 3-4 observed toxic effects per patient were neutropenia (60%), asymptomatic liver toxicity (13.5%), asthenia (14%) and hand-foot syndrome (16%). Only one patient presented febrile neutropenia. No treatment-related deaths occurred. CONCLUSION: Combination of gemcitabine and capecitabine is an active and safe regimen in anthracycline-pretreated breast cancer patients.

PMID: 19940004 [PubMed - as supplied by publisher]






Med Oncol. 2009 Jun 13. [Epub ahead of print]
Prospective phase II study of neoadjuvant doxorubicin followed by cisplatin/docetaxel in locally advanced breast cancer.

Al-Tweigeri TA, Ajarim DS, Alsayed AA, Rahal MM, Alshabanah MO, Tulbah AM, Al-Malik OA, Fatani DM, El-Husseiny GA, Elkum NB, Ezzat AA.
Department of Medical Oncology, King Faisal Specialist Hospital and Research Centre, Oncology Centre, MBC 64, P.O. Box 3354, Riyadh, 11211, Kingdom of Saudi Arabia, ttwegieri@kfshrc.edu.sa.
The objective of this study is to evaluate the efficacy and safety profile of the doxorubicin followed by cisplatin/docetaxel as primary chemotherapy for patients with locally advanced breast cancer (LABC). For this evaluation, 59 patients with LABC (T2-T4, N0-N2, M0) received three cycles of doxorubicin, followed by three cycles of cisplatin/docetaxel and followed by definitive surgery and locoregional radiotherapy with or without tamoxifen. The primary end point was pathologic complete response (pCR) in breast and axilla. Fifty-nine patients were evaluable for analysis: median age: 41 years, premenopausal: 68%, median tumor size: 6.0 cm (4-10), Stage IIB: 32% and IIIA/IIIB: 68%, both ER/PR positive: 53%, Her2/neu (3+) by IHC staining: 29%. Clinical complete response was seen in 44%, and clinical partial response was seen in 56%. Breast conserving surgery was performed in 44%, and MRM in 56%. pCR in the breast was 30.5%, in axilla was 37%, and pCR in both breast and axilla was 24%. Overall at follow-up of 60 months, the disease-free (DFS) and overall survival (OS) were 70 and 82%, respectively. The DFS and OS of patients who achieved complete pathologic response in breast and axilla were 78 and 100%, respectively, while 14 patients relapsed of which 46% were Her2 positive. Sequential combination of doxorubicin followed by docetaxel/cisplatin is a safe, feasible, and active combination, which offers the possibility of conservative surgery and is associated with high clinical and pathologic response rates, with promising and encouraging survival outcomes.

PMID: 19526202 [PubMed - as supplied by publisher]



Breast Cancer Res Treat. 2009 Jul;116(2):351-8. Epub 2008 Oct 22.
Non-pegylated liposomal doxorubicin combined with gemcitabine as first-line treatment for metastatic or locally advanced breast cancer. Final results of a phase I/II trial.

Del Barco S, Colomer R, Calvo L, Tusquets I, Adrover E, Sánchez P, Rif* J, De la Haba J, Virizuela JA.
Institut Catal* d'Oncologia (ICO), Hospital Universitario Josep Trueta, Girona, Spain, sdelbarco@ico.scs.es.
Doxorubicin and gemcitabine are active as single agents in breast cancer, have different mechanisms of action, and mainly have non-overlapping side effects. Dose-dependent doxorubicin-related cardiac toxicity is the principal limitation in the metastatic setting. This open, multicenter, single-arm phase I/II study assessed the safety and activity of gemcitabine in combination with non-pegylated liposomal doxorubicin (Myocet), a more cardiac-friendly anthracycline, in the first-line treatment of patients with advanced breast cancer. We aimed to determine the optimal recommended dose (RD) of gemcitabine combined with Myocet in a population, with performance status >or=2 and LVEF >or=50%. A formal phase II study was performed afterwards. A total of 53 patients were recruited. Gemcitabine 900 mg/m(2) intravenously day 1 and 8 combined with Myocet 55 mg/m(2) intravenously day 1, every 21 days, was the final RD. The principal toxicity observed was hematological, and 48% of patients developed grade 3-4 neutropenia. Other toxicities were mild and infrequent, including nausea and vomiting. There were no symptomatic cardiac events despite the fact that 36% of the patients had received prior treatment with adjuvant anthracyclines. Objective responses were observed in 51.1% of 47 evaluable patients (95% CI: 36-66%), including two complete response. In addition, 14 patients (29.8%) demonstrated stable disease. The combination of Myocet and gemcitabine at the RD is safe and has encouraging clinical activity in patients with advanced breast cancer, without apparent cardiac toxicity in anthracycline-pretreated patients. These data support further development of this combination.

PMID: 18941891 [PubMed - indexed for MEDLINE]





Ann Oncol. 2009 Mar;20(3):449-53. Epub 2008 Dec 15.
Phase II trial of weekly nab (nanoparticle albumin-bound)-paclitaxel (nab-paclitaxel) (Abraxane) in combination with gemcitabine in patients with metastatic breast cancer (N0531).

Roy V, LaPlant BR, Gross GG, Bane CL, Palmieri FM; North Central Cancer Treatment Group.
Division of Hematology-Oncology, Mayo Clinic, Jacksonville, FL 32224, USA. roy.vivek@mayo.edu
Nanoparticle albumin-bound (nab)-paclitaxel has better efficacy and practically eliminates the risk of hypersensitivity reactions associated with solvent-based paclitaxel. We studied weekly nab-paclitaxel and gemcitabine combination in an open-label one-stage, phase II trial in patients with previously untreated metastatic breast cancer (MBC). Nab-paclitaxel (125 mg/m(2)) and gemcitabine (1000 mg/m(2)) were administered on days 1 and 8 of a 21-day cycle until disease progression. Fifty patients were enrolled. Forty (80%) had visceral organ involvement and 30 (60%) had >or= 3 sites of metastases. Four (8%) and 21 (42%) patients had complete and partial responses by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Median duration of response was 6.9 months [95% confidence interval (CI) 5.7, not reached], median progression-free survival (PFS) 7.9 months (95% CI 5.4-10 months), and median overall survival (OS) was not reached. PFS and OS at 6 months were 60% (95% CI 48% to 76%) and 92% (95% CI 85% to 100%), respectively. Therapy was well tolerated. Neutropenia was commonest toxicity (42% and 12% grades 3 and 4 neutropenia). Only one patient developed febrile neutropenia. Significant activity and favorable toxicity profile provides a basis for considering this regimen for further evaluation in phase III trials or in combination with biologic agents.

PMID: 19087987 [PubMed - indexed for MEDLINE]

Related focus on mechanisms:

Treatment for Pancreatic Cancer May Target Tumor Microenvironment

Researchers have found some clues to suggest why combining nab-paclitaxel (Abraxane) with gemcitabine may be a more effective treatment for advanced pancreatic cancer than gemcitabine alone, the current standard of care.
This spring, updated results from an early stage clinical trial testing the combination therapy showed a promising response, particularly in patients whose tumors produced an abundance of the protein known as SPARC. Results from a mouse model study presented today at the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics conference in Boston indicate that adding nab-paclitaxel to gemcitabine may improve response to treatment in part by altering the supportive tissue around the tumor, or stroma, allowing more gemcitabine to reach tumor cells.
The finding “shows that effective treatment does not necessarily require a fancy new molecular therapy, but just the smart combination of what is already available,” said the study’s lead investigator, Dr. Anirban Maitra from the Johns Hopkins University School of Medicine. Gemcitabine is the standard first-line treatment for pancreatic cancer, and nab-paclitaxel, a different form of paclitaxel (Taxol) that is bound to the protein albumin to improve its delivery, is approved for metastatic breast cancer.
To conduct the study, the research team tested the combination in pancreatic cancer mouse models generated at Johns Hopkins. Mice that received the combination were twice as likely to respond to the treatment as those that received gemcitabine alone, with an overall response rate (at least some tumor shrinkage) of 57 percent. They also found that mice given the combination therapy had significantly less of the “abundant fibrotic stroma” that typically surrounds pancreatic tumors and which was always seen in mice given only gemcitabine or no treatment at all.
Quote:
The concentration of gemcitabine in tumors from mice that received the combination therapy was 3.7-fold higher than in the animals given only gemcitabine.
Nab-paclitaxel was recently granted orphan drug status by the FDA (making it eligible for expedited FDA review and extended patent protection, among other things) for use in patients with pancreatic cancer and advanced melanoma. Enrollment is currently open for a phase III trial for pancreatic cancer that will compare gemcitabine plus nab-paclitaxel against gemcitabine alone.



J Clin Oncol. 2006 Apr 20;24(12):1831-8. Epub 2006 Mar 20.
Docetaxel, cisplatin, and trastuzumab as primary systemic therapy for human epidermal growth factor receptor 2-positive locally advanced breast cancer.

Hurley J, Doliny P, Reis I, Silva O, Gomez-Fernandez C, Velez P, Pauletti G, Powell JE, Pegram MD, Slamon DJ.
Sylvester Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. jhurley@miami.edu
Erratum in:
  • J Clin Oncol. 2006 Jul 20;24(21):3515. Powell, Jodeen E [added].
PURPOSE: To evaluate the efficacy and safety of docetaxel, cisplatin, and trastuzumab as primary systemic therapy for human epidermal growth factor receptor 2 (HER2) -positive, locally advanced breast cancer (LABC). PATIENTS AND METHODS: Forty-eight patients with immunohistochemistry-confirmed HER2-positive LABC or inflammatory breast cancer received 12 weeks of docetaxel, cisplatin, and trastuzumab with filgrastim, followed by surgery, adjuvant doxorubicin and cyclophosphamide, and locoregional radiotherapy with or without tamoxifen. The primary end point was pathologic complete response (pCR) in breast. RESULTS: Baseline mean tumor size was 9.2 cm (range, 4 to 32 cm). pCR occurred in breast in 11 patients (23%; 95% CI, 12% to 37%) and breast and axilla in eight patients (17%; 95% CI, 8% to 30%). pCR rates in breast (HER2 positive, seven of 30 patients, 23% v HER2 negative, four of 18 patients, 22%; P > .05) and breast and axilla (four of 30 patients, 13% v four of 18 patients, 22%, respectively; P > .05) were similar regardless of HER2 status by fluorescence in situ hybridization (FISH). At a median follow-up time of 43 months, 4-year progression-free survival (PFS) rate was 81% (95% CI, 64% to 90%); overall survival (OS) rate was 86% (95% CI, 71% to 94%). In patients with pCR in breast and axilla, PFS and OS rates were 100% (95% CI, inestimable). In patients without pCR, PFS rate was 76% (95% CI, 57% to 88%; P = .15, log-rank test), and OS rate was 83% (95% CI, 66% to 92%; P = .21). Survival rates were similar regardless of FISH status. There were only two grade 4 adverse events. CONCLUSION: Twelve weeks of docetaxel, cisplatin, and trastuzumab is clinically active and leads to excellent survival in patients with large, HER2-positive tumors.

PMID: 16549824 [PubMed - indexed for MEDLINE]



LINK

Dasatinib Plus Doxorubicin Effectively Blocks Spread of Breast Cancer Cells

Tasheema Prince
December 09 2009

When dasatinib is added to a commonly used breast cancer drug, it helps prevent breast cancer cells from invading organs, say researchers who published their study in the British Journal of Cancer (2009;101[1]:38-47).
In the study, conducted by Seth Corey, MD, of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, dasatinib, a drug normally used to treat leukemia, was combined with doxorubicin to evaluate the whether or not critical cancer cell functions were blocked.
Dr Corey found that the potent chemotherapy cocktail inhibited breast cancer cell invasion by half. In the press release announcing the study, the authors explained that dasatinib targets an enzyme called the Src kinase, which is believed to play a key role in breast cancer invasion and metastases. According to the release, there are currently no drugs that specifically target the invasion and spread of breast cancer to the organs.
“This is an entirely new way of targeting a cancer cell,” said Dr Corey. “Perhaps this drug could be given to prevent invasion from happening in the first place. This might keep the disease in check and prevent it from progressing.”




Docetaxel Plus Capecitabine Shows More Benefit as First-Line Therapy for Metastatic Breast Cancer Than Docetaxel Plus Epirubicin: Presented at SABCS

By Jennifer Reising
LINK
SAN ANTONIO, Tex -- December 12, 2009 -- The combination of docetaxel and capecitabine is associated with an increased nonprogression rate at 6 months and a longer progression-free survival (PFS) and overall survival (OS) than docetaxel plus epirubicin as a first-line treatment for metastatic breast cancer, according to the final results of a study presented here on December 11 at the 32nd Annual San Antonio Breast Cancer Symposium (SABCS).

"Our study shows that docetaxel and capecitabine is superior to docetaxel plus epirubicin in the first-line of treatment for women with metastatic breast cancer," said Thomas Bachelot, MD, PhD, Centre Léon Bérard, Lyon, France. "There appears to be no gain in including anthracyclines, such as epirubicin, in the first line of treatment for this group of patients."

Nonprogression at 6 months after randomisation was the primary endpoint of the Etude de phase III comparant l'efficacité de 2 stratégies thérapeutiques de chimiothérapie chez des patientes atteintes d'un cancer du sein métastatique (ERASME-4). The main secondary endpoints were PFS and OS.

Between June 2004 and April 2006, 68 patients with metastatic breast cancer who were previously untreated with chemotherapy were randomised to receive either DC (docetaxel 75 mg/m2 intravenously on day 1 and oral capecitabine 1,000 mg/m2 twice daily on days 1 to 14 every 3 weeks) or DE (docetaxel 75 mg/m2 intravenously and epirubicin 75 mg/m2 intravenously on day 1 every 3 weeks).

Study results demonstrated that 6 months after treatment, 75.8% (95% confidence interval [CI], 57.7%-88.9%) of patients who were treated in the DC arm were progression free, compared with 65.7% (95% CI, 47.8%-80.9%) in the DE arm. After a medium follow-up of 42 months (95% CI, 32.5-21.1), the median progression-free survival was 12.4 months in the DC group, compared with 6.8 months in the DE group (P = .04). The median OS was 37 months for the DC arm versus 27 months for the DE arm (P = .49).

"The combination of docetaxel and capecitabine may be a valid alternative to adding epirubicin to docetaxel -- especially for those patients who have been previously exposed to an anthracycline therapy in the adjuvant setting and for those who are unable to be treated with bevacizumab," said Dr. Bachelot.

Funding for this study was provided by Roche France and sanofi-aventis France.

[Presentation title: Superiority of Docetaxel + Capecitabine Compared to Docetaxel + Epirubicin as First-Line Therapy for Metastatic Breast Cancer - Final Results of the ERASME-4 Study. Abstract 2099]



ASCO Breast: Low-Dose, Rapid-Cycle Chemotherapy Active Against Anthracycline- Resistant Disease

WASHINGTON -- For patients with anthracycline-resistant breast cancer, continuous treatment with weekly low-dose docetaxel (Taxotere) plus daily capecitabine (Xeloda) provided a clinical benefit greater than 40%.


Certain drug treatments favored for breast cancer

Tuesday, Dec. 9, 2008; 5:26 PM

LONDON (Reuters) - Greek researchers have identified the chemotherapy combinations that appear to help women with advanced breast cancer live longest, they reported on Tuesday.
Women who took a combination of a taxane-based therapy such as Taxol or paclitaxel, or Sanofi Aventis' Taxotere, known generically as docetaxel, with other drugs lived a year longer than women who did not get chemotherapy.
Women given either a single taxane drug or a combination that included an anthracycline such as Adriamycin with older chemotherapy drugs lived an extra eight months compared to untreated women, said John Ioannidis of the University of Ioannina School of Medicine in Greece.
The findings are the first to compare different chemotherapy treatments used over the past 35 years to gauge how effective they are, he added.
"The main message is this is one type of cancer where we do have a number of treatments that are effective, said Ioannidis, who led the study published in the Journal of the National Cancer Institute.
"What is new is the quantification and being able to put a number on how much is the benefit for what is available," Ioannidis told Reuters in a telephone interview.
Breast cancer is the leading cause of cancer death among women worldwide, according to the American Cancer Society. The group estimates about 465,000 women died of breast cancer worldwide in 2007 and 1.3 million new cases were diagnosed.
Declining death rates from the disease in developed countries have been attributed to early detection through mammography screening and to improved treatment.
One widespread treatment is the generic pill tamoxifen, which blocks oestrogen from fueling tumours. Another treatment that targets hormones is a class of drugs called aromatase inhibitors such as AstraZeneca Plc's Arimidex.
Ioannidis and his team analysed 128 clinical trials involving more than 26,000 women who received chemotherapy drugs which kill cancer cells directly rather than target hormones. The review included 148 comparisons of different treatments.
The findings are also a step toward finding consensus on the best dosage, timing and sequence or combination of different treatments, the researchers added.


Erbitux, Celebrex & experimental anti-inflammatory



Halting Breast Cancer Spread

(RRC - RI) -- New York researchers say drugs targeting four genes may stop breast cancer from spreading to the lungs. The troublesome genes -- the EREG gene, the Cox-2 gene, the MMP1 gene and the MMP2 gene -- may be necessary for cancer to spread.

Scientists at Howard Hughes Medical Institute and the Cancer Biology and Genetics Program at New York's Memorial Sloan Kettering Cancer Center used three drugs, the cancer drug Erbitux, the anti-inflammatory drug Celebrex, and an experimental anti-inflammatory drug to target the four genes in mice, which had been injected with breast cancer cells.

Cancer cells where all four genes were inactivated had difficulty growing new blood vessels and this stopped cancer from spreading into the lungs. However, in mice where only one of the genes was inactivated, the cancer had no trouble spreading.

Clinical trials of the drug combination are being discussed.

http://www.robertsreview.com/#Gene_t...lanoma_cancers



http://www.hhmi.org/news/massague20070412.html


April 12, 2007
A Genetic "Gang of Four" Drives Spread of Breast Cancer Studies of human tumor cells implanted in mice have shown that the abnormal activation of four genes drives the spread of breast cancer to the lungs. The new studies by Howard Hughes Medical Institute researchers reveal that the aberrant genes work together to promote the growth of primary breast tumors. Cooperation among the four genes also enables cancerous cells to escape into the bloodstream and penetrate through blood vessels into lung tissues.
Although shutting off these genes individually can slow cancer growth and metastasis, the researchers found that turning off all four together had a far more dramatic effect on halting cancer growth and metastasis. Metastasis occurs when cells from a primary tumor break off and invade another organ. It is the deadliest transformation that a cancer can undergo, and therefore researchers have been looking for specific genes that propel metastasis.

“While silencing these genes individually was effective, silencing the quartet nearly completely eliminated tumor growth and spread.”
Joan Massagué
In the newly published experiments, the researchers also found that they could reduce the growth and spread of human breast tumors in mice by simultaneously targeting two of the proteins produced by these genes, using drugs already on the market. The researchers are exploring clinical testing of combination therapy with the drugs—cetuximab (trade name Erbitux) and celecoxib (Celebrex)—to treat breast cancer metastasis.
The research team, led by Howard Hughes Medical Institute investigator Joan Massagué at the Memorial Sloan-Kettering Cancer Center, published its findings in articles in the April 12, 2007, issue of the journal Nature and in the online early edition of the Proceedings of the National Academy of Sciences on April 9, 2007.


Clinical Study
Capecitabine and Mitomycin C Is an Effective Combination for Anthracycline- and Taxane-Resistant Metastatic Breast Cancer
Cristian Massacesia, Annalisa La Cesab, Fabiana Marcuccia, Alberta Pilonea, Marco B.L. Rocchic, Laura Zepponia, Daniele Santinib, Giuseppe Toninib, Luciano Burattinia

aDepartment of Oncology and Radiotherapy, Ospedali Riuniti, Ancona,
bMedical Oncology, Universit* Campus Biomedico, Rome, and
cBiomathematics Institute, Universit* di Urbino, Urbino, Italy

Address of Corresponding Author
Oncology 2006;70:294-300 (DOI: 10.1159/000096250)


Abstract
Capecitabine is converted to 5-fluorouracil by thymidine phosphorylase, and mitomycin C is capable of upregulating the expression of thymidine phosphorylase suggesting a synergistic effect. Fifty-three patients (median age 62 years) with anthracycline- and taxane-resistant, metastatic breast cancer received mitomycin C 6 mg/m2 on day 1, and capecitabine (Xeloda) 2,000 mg/m2/day from day 1 to day 14 with cycles repeated every 4 weeks. Overall, 77.4% had visceral metastases and 33 were pretreated with 3 chemotherapy lines. A median of 6 cycles were given (range 1-19) with a complete response observed in 2 patients (3.9%), partial response in 17 (33.3%) and stable disease in 19 (37.2%). Overall response rate was 37.2% (95% CI, 24.0-50.5%), with a median duration of 10.4 months. Median time to progression was 8.1 months and median survival was 17.4 months (1- and 2-year survival rates of 60 and 28%, respectively). Toxicity was mild. The most frequent grade 3/4 events were neutropenia (5.7% of patients), diarrhea (3.8%), and deep venous thrombosis (3.8%). Capecitabine plus mitomycin C may represent an effective and manageable treatment option for advanced breast cancer patients resistant to anthracyclines and taxanes. This approach provides an alternative for pretreated patients with advanced breast cancer.
Copyright © 2006 S. Karger AG, Basel

Author Contacts
Cristian Massacesi, MD
Department of Oncology and Radiotherapy, Ospedali Riuniti
Via Conca 71, IT-60020 Ancona (Italy)
Tel. +39 071 596 4260, Fax +39 071 596 4837
E-Mail c.massacesi@ao-umbertoprimo.marche.it


Tumori. 2009 Nov-Dec;95(6):683-6.
Mitomycin C and vinblastine: an active regimen in previously treated breast cancer patients.

Ospovat I, Siegelmann-Danieli N, Grenader T, Hubert A, Hamburger T, Peretz T.
Department of Oncology, Hadassah University Hospital, Jerusalem, Israel. innaospovat@gmail.com
BACKGROUND: Metastatic breast cancer has a substantial mortality burden on women worldwide. Presented herein is our experience with the combination of mitomycin-C and vinblastine in heavily pretreated breast cancer patients. METHODS: Candidates were women with measurable metastatic disease, previously exposed to two or more chemotherapy regimens. Mitomycin-C was given at the dose of 10 mg/m2 on day 1 and vinblastine at 6 mg/m2 on days 1 and 21 of each 42-day cycle. Analysis included patients exposed to one or more cycles of therapy. Kaplan-Meier curves were used to generate overall survival and time-to-treatment progression curves. RESULTS: Forty patients previously exposed to a median of three prior regimens were included. Partial response and stable disease were reported in 14 (35%) and 10 (25%), patients, respectively, for a clinical benefit of 60%. With a median follow-up of 11 months, the median time to progression and survival durations lasted 4 and 12 months, respectively. In a subgroup of 17 women with prior anthracycline and taxane exposure, partial response and stable disease were reported in 4 (23.5%) and 5 (29%), respectively. Treatment was generally well tolerated, with grade 3-4 hematologic and non-hematologic toxicity reported in 8 (20%) and 3 (7.5%) patients, respectively. Two cases of fatalities (5%) occurred with pulmonary toxicity in women heavily exposed to mitomycin-C (cumulative doses of > or = 40 mg/m2) and soon after red blood cell transfusion. CONCLUSIONS: Chemotherapy with mitomycin-C and vinblastine is active and well-tolerated in heavily pretreated breast cancer patients. Caution should be taken to avoid blood transfusion alone with mitomycin-C therapy.

PMID: 20210229 [PubMed - in process]







Gan To Kagaku Ryoho. 2009 Feb;36(2):333-5.


A case of metastatic breast cancer with liver metastasis effectively treated with capecitabine and vinorelbine



[Article in Japanese]
Inari H, Chiba A, Inaba M, Ino H, Fukahori M, Yoshida A.
Division of Breast and Thyroid Surgery, Kanagawa Cancer Center.
A 31-year-old woman with cancer of the right breast underwent surgery in 1996. Histological examination demonstrated a solid tubular carcinoma that was positive lymph node metastasis and hormonal receptor, but negative for HER2 expression. The patient underwent adjuvant therapy with CAF and tamoxifen. At the age of 40 years old, Multiple liver metastasis appeared to the patient. We treated her with paclitaxel. But multiple liver metastasis became progressive disease. Next we treated with capecitabine and vinorelbine. The liver metastasis reduced, and, in the eighth month, the liver metastasis disappeared after 9 cycles. We changed treatment to goserelin, and anastrozole. The period of complete response was 1 year 3 months.

PMID: 19223759 [PubMed - indexed for MEDLINE]


1: Cancer Res. 2008 Sep 1;68(17):7083-9.
FULL TEXT
Synergistic inhibition with a dual epidermal growth factor receptor/HER-2/neu tyrosine kinase inhibitor and a disintegrin and metalloprotease inhibitor.

Witters L, Scherle P, Friedman S, Fridman J, Caulder E, Newton R, Lipton A.
Department of Medicine, The Milton S. Hershey Medical Center/Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
The ErbB family of receptors is overexpressed in numerous human tumors. Overexpression correlates with poor prognosis and resistance to therapy. Use of ErbB-specific antibodies to the receptors (Herceptin or Erbitux) or ErbB-specific small-molecule inhibitors of the receptor tyrosine kinase activity (Iressa or Tarceva) has shown clinical efficacy in several solid tumors. An alternative method of affecting ErbB-initiated tumor growth and survival is to block sheddase activity. Sheddase activity is responsible for cleavage of multiple ErbB ligands and receptors, a necessary step in availability of the soluble, active form of the ligand and a constitutively activated ligand-independent receptor. This sheddase activity is attributed to the ADAM (a disintegrin and metalloprotease) family of proteins. ADAM 10 is the main sheddase of epidermal growth factor (EGF) and HER-2/neu cleavage, whereas ADAM17 is required for cleavage of additional EGF receptor (EGFR) ligands (transforming growth factor-alpha, amphiregulin, heregulin, heparin binding EGF-like ligand). This study has shown that addition of INCB3619, a potent inhibitor of ADAM10 and ADAM17, reduces in vitro HER-2/neu and amphiregulin shedding, confirming that it interferes with both HER-2/neu and EGFR ligand cleavage. Combining INCB3619 with a lapatinib-like dual inhibitor of EGFR and HER-2/neu kinases resulted in synergistic growth inhibition in MCF-7 and HER-2/neu-transfected MCF-7 human breast cancer cells. Combining the INCB7839 second-generation sheddase inhibitor with lapatinib prevented the growth of HER-2/neu-positive BT474-SC1 human breast cancer xenografts in vivo. These results suggest that there may be an additional clinical benefit of combining agents that target the ErbB pathways at multiple points.
PMID: 18757423 [PubMed - indexed for MEDLINE

Large Open-label Expanded Access Study Confirms Effectiveness of Tykerb® and Xeloda® in Metastatic HER2+ Breast Cancer‏


Large Open-label Expanded Access Study Confirms Effectiveness of Tykerb® and Xeloda® in Metastatic HER2+ Breast CancerResearchers involved in the LEAP (Lapatinib Expanded Access Program) international trial have reported that Tykerb® (lapatinib) and Xeloda® (capecitabine) is effective and safe for the treatment of patients with HER2-positive (HER2+) over-expressing locally advanced or metastatic breast cancer who had previously failed treatment with an anthracycline, a taxane, and Herceptin® (trastuzumab). The details of this study appeared early online in the Annals of Oncology on October 8, 2009.[1]
Tykerb is an oral small molecule that targets both ErbB1 and ErbB2 tyrosine kinases. Tykerb has demonstrated activity in HER2-positive breast cancers and continues to be evaluated in different patient populations. Randomized trials have shown that Tykerb plus Xeloda is more effective than Xeloda alone in patients with HER2+ breast cancer who have failed treatment with an anthracycline, a taxane, and Herceptin. The current study was undertaken to determine if the results of Tykerb and Xeloda treatment hold up when evaluated in a broader population.
The current study was an open-label expanded access study involving 4,283 patients with HER2+ locally advanced or metastatic breast cancer treated in 45 countries. All had failed an anthracycline, a taxane, and Herceptin. The average treatment time was 25 weeks. The most common grade 3-4 side effects reported were diarrhea, vomiting, and nausea; all occurring with a frequency of <10%. Decreased left ventricle ejection fraction occurred in 0.5%, interstitial pneumonitis occurred in 0.2%, and serous hepatic problems in 0.4%. The median progression-free survival was 21 weeks, and the median overall survival was 39.6 weeks. Patients who had not been previously treated with Xeloda had longer survivals.
Comment: This large study validates the results of randomized trials showing improvement of progression-free and overall survival with acceptable toxicity following treatment with Tykerb and Xeloda compared with Xeloda alone.
Reference:
[1] Capri G, Chang J, Chen S-C, et al. An open-label expanded access study of lapatinib and capecitabine in patients with HER2-overexpressing locally advanced or metastatic breast cancer. Annals of Oncology [early online publication] 2009; on October 8.


We found 1 article by title matching your search:





Breast Cancer. 2007;14(3):297-301.
Complete remission of recurrent breast cancer with multiple liver metastases after oral capecitabine and injected trastuzumab.

Morohashi S, Odagiri H, Morohashi H, Kimura Y, Sasaki M.
Department of Surgery, Hirosaki University School of Medicine, Hirosaki, Japan. hm2002@cc.hirosaki-u.ac.jp
A 32-year-old woman underwent modified radical mastectomy for right breast cancer (invasive ductal carcinoma, f, INF beta, v0, ly1, pT2, pN1, M0, Stage II B ER (+/-), PR (-), Her2 (3+)) in June 2003, and received postoperative systemic adjunctive chemotherapy using epirubicin combined with cyclophosphamide, followed by paclitaxel. In August 2004, after a disease-free interval of 14 months, liver metastasis appeared, and therefore from September 2004, combination chemotherapy with oral capecitabine (2,400 mg/day) and injected trastuzumab (120 mg/week) was started. After 3 cycles, all the metastases responded and this marked response has been maintained for 16 months. This therapy is currently being continued (19 cycles), and no serious side effects have been encountered. Capesitabine and trastuzumab combination therapy is effective for recurrent breast cancer showing overexpression of HER2 and resistance to taxane, and can be considered as a first-line therapy for this purpose. It is anticipated that many cases treated with this regimen will be reported and discussed in the near future.

PMID: 17690508 [PubMed - indexed for MEDLINE]


http://jco.ascopubs.org/cgi/content/full/25/33/5210
Ixabepilone Plus Capecitabine for Metastatic Breast Cancer Progressing After Anthracycline and Taxane Treatment

Eva S. Thomas, Henry L. Gomez, Rubi K. Li, Hyun-Cheol Chung, Luis E. Fein, Valorie F. Chan, Jacek Jassem, Xavier B. Pivot, Judith V. Klimovsky, Fernando Hurtado de Mendoza, Binghe Xu, Mario Campone, Guillermo L. Lerzo, Ronald A. Peck, Pralay Mukhopadhyay, Linda T. Vahdat, Henri H. Roché
From the M.D. Anderson Cancer Center, Houston, TX; Instituto Nacional de Enfermedades Neoplasicas; Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru; St Luke's Medical Center; Veterans Memorial Medical Center, Quezon City, Philippines; Yonsei Cancer Center, Seoul, Republic of Korea; Centro de Oncologia Rosario, Sante Fe; Hospital de Oncologia ‘Maria Curie,’ Buenos Aires, Argentina; Medical University of Gdansk, Gdansk, Poland; C.H.U. Jean Minjoz, Besançon; Centre Rene Gauducheau, Nantes; Institut Claudius Regaud, Toulouse, France; Bristol-Myers Squibb, Research and Development, Wallingford, CT; Cancer Hospital –Chinese Academy of Medical Sciences, Beijing, China; and Weill Medical College of Cornell University, New York, NY
Address reprint requests to Eva S. Thomas, MD, 280 West MacArthur Blvd, Oakland, CA 94611; e-mail: eva.s.thomas@kp.org
Purpose Effective treatment options for patients with metastatic breast cancer resistant to anthracyclines and taxanes are limited. Ixabepilone has single-agent activity in these patients and has demonstrated synergy with capecitabine in this setting. This study was designed to compare ixabepilone plus capecitabine versus capecitabine alone in anthracycline-pretreated or -resistant and taxane-resistant locally advanced or metastatic breast cancer.
Patients and Methods Seven hundred fifty-two patients were randomly assigned to ixabepilone 40 mg/m2 intravenously on day 1 of a 21-day cycle plus capecitabine 2,000 mg/m2 orally on days 1 through 14 of a 21-day cycle, or capecitabine alone 2,500 mg/m2 on the same schedule, in this international phase III study. The primary end point was progression-free survival evaluated by blinded independent review.
Results Ixabepilone plus capecitabine prolonged progression-free survival relative to capecitabine (median, 5.8 v 4.2 months), with a 25% reduction in the estimated risk of disease progression (hazard ratio, 0.75; 95% CI, 0.64 to 0.88; P = .0003). Objective response rate was also increased (35% v 14%; P < .0001). Grade 3/4 treatment-related sensory neuropathy (21% v 0%), fatigue (9% v 3%), and neutropenia (68% v 11%) were more frequent with combination therapy, as was the rate of death as a result of toxicity (3% v 1%, with patients with liver dysfunction [ grade 2 liver function tests] at greater risk). Capecitabine-related toxicities were similar for both treatment groups.

Conclusion

Ixabepilone plus capecitabine demonstrates superior efficacy to capecitabine alone in patients with metastatic breast cancer pretreated or resistant to anthracyclines and resistant to taxanes.



J Cancer Res Clin Oncol. 2009 Apr;135(4):643-7. Epub 2008 Oct 21.
Monitoring circulating epithelial tumour cells (CETC) to gauge therapy: in patients with disease progression after trastuzumab persisting CETC can be eliminated by combined lapatinib treatment.

Camara O, Jörke C, Hammer U, Egbe A, Rabenstein C, Runnebaum IB, Hoeffken K, Pachmann K.
Women's Hospital, Friedrich Schiller University, Bachstr. 18, 07740, Jena, Germany.
BACKGROUND: In breast cancers, the gene for the growth factor receptor HER2 can be amplified leading to increased aggressiveness and metastasis formation. The monoclonal antibody trastuzumab prolongs relapse-free survival highly significantly but eventually many patients relapse. METHOD: In this study, CETC were monitored using the Maintrac method during adjuvant trastuzumab treatment and during subsequent treatment with capecitabine/lapatinib. RESULTS: In one patient, trastuzumab led to marginal reduction in CETC with disease progress. The combination of capecitabine/lapatinib was preliminarily capable to eliminate all CETC, however, CETC reappeared. The second patient received adjuvant taxane together with trastuzumab and 1 year of further trastuzumab during which CETC increased. After stopping trastuzumab skin metastases occurred. Capecitabine/lapatinib led to complete CETC elimination with stable disease. CONCLUSIONS: In patients with lack of CETC reduction in spite of trastuzumab treatment correlated with disease progression the combination of capecitabine/lapatinib highly efficiently led to rapid elimination of CETC warranting further monitoring during such studies.

PMID: 18936973 [PubMed - indexed for MEDLINE]



Lancet Oncol. 2010 Feb 15. [Epub ahead of print]
Activity of a multitargeted chemo-switch regimen (sorafenib, gemcitabine, and metronomic capecitabine) in metastatic renal-cell carcinoma: a phase 2 study (SOGUG-02-06).

Bellmunt J, Trigo JM, Calvo E, Carles J, Pérez-Gracia JL, Rubió J, Virizuela JA, López R, Lázaro M, Albanell J.
University Hospital del Mar-IMIM, Barcelona, Spain.
BACKGROUND: Maximum tolerated dose (MTD) chemotherapy followed by metronomic chemotherapy (low doses given on a frequent schedule) acts on tumour vascular endothelial cells by increasing the anti-tumour effect of anti-angiogenic agents. This multicentre, phase 2 study investigated the effectiveness of MTD gemcitabine combined with metronomic capecitabine plus the multikinase inhibitor sorafenib for the treatment of metastatic renal-cell carcinoma (RCC). METHODS: Patients were enrolled at eight centres across Spain between Dec 13, 2006, and April 17, 2008. Patients were aged 18 years or older, had confirmed metastatic RCC with clear-cell histology, had an Eastern Cooperative Oncology Group performance status of 0 or 1, had not undergone previous therapy, and were unsuitable for, or intolerant to, immunotherapy. Treatment consisted of intravenous gemcitabine 1000 mg/m(2) (days 1 and 8), oral capecitabine 500 mg/m(2) twice a day (final dose after adjustment, days 1-14), and oral sorafenib 400 mg twice a day (days 1-21), for six cycles, followed by sorafenib monotherapy (at the investigator's discretion if clinical benefit was maintained). The primary endpoint was median progression-free survival (PFS) analysed in a population of all patients who received treatment. The trial is registered with ClinicalTrials.gov, number NCT00496301. FINDINGS: 44 patients enrolled in the study, 40 of whom received treatment. Median PFS for these patients was 11.1 months (95% CI 7.9-17.1). A partial response was achieved in 20 patients, and stable disease in 17 patients. Most adverse events were grade 1 or 2. Grade 3 adverse events were fatigue or asthenia (n=9), hand-foot skin reaction (n=11), mucositis (n=3), diarrhoea (n=2), infection (n=2), and allergic reaction, hypertension, and rash (all n=1). Grade 3 haematological toxicity was noted in nine patients. One death due to pulmonary embolism was reported as grade 5 dyspnoea possibly related to study drug. INTERPRETATION: PFS and response rates were greater than those previously observed with gemcitabine and capecitabine or sorafenib monotherapy in patients with metastatic RCC. Adverse events were manageable in most patients. These findings provide preliminary confirmation of the synergistic activity of the chemo-switch concept seen in preclinical studies, and merit further exploration. FUNDING: Spanish Oncology Genitourinary Group (SOGUG). Copyright © 2010 Elsevier Ltd. All rights reserved.

PMID: 20163987 [PubMed - as supplied by publisher]




Curr Oncol. 2010 Apr;17(2):64-8.
One year of complete clinical response in a metastatic breast cancer patient treated with a combination of lapatinib and gemcitabine.

Gasent Blesa JM, Laforga Canales J, Candel VA.
Abstract

The treatment of metastatic breast cancer is challenging. We recently assisted in the development of targeted therapies (in combination with chemotherapy or as monotherapy) that have improved results for selected groups of patients. Lapatinib is a dual tyrosine kinase inhibitor that has shown efficacy in breast cancer. Consequently, its use has been approved, in combination with capecitabine, for the treatment of disease positive for the human epidermal growth factor receptor. Here, we present a case of complete clinical response to a combination of lapatinib and gemcitabine that was maintained for 1 year.

PMID: 20404981 [PubMed - in process]
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Old 07-06-2010, 09:57 AM   #2
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Re: Chemo Combinations/sequences with oomph

Cancer. 1983 Jun 1;51(11):1998-2004.
Prolonged remissions of metastatic breast cancer achieved with a six-drug regimen of relatively low toxicity.
Hirshaut Y, Kesselheim H.


FREE TEXT

Abstract
A combination of six chemotherapeutic agents was used to treat 30 women with unresectable metastatic carcinoma of the breast. In the first year five drugs (Cytoxan, methotrexate, 5-fluorouracil, vincristine, and prednisolone [CMFVP]) were given using a weekly schedule for administration of intravenous drugs. During the next year, a seven-week treatment cycle was introduced, with CMFVP given for four weeks, followed by an Adriamycin combination (Adriamycin, cyclophosphamide, and prednisone [ACP]) for three weeks and then the cycle repeated. Treatment was continued for three years or to time of relapse. Overall response rate was 66.7% (20/30). The median duration of response was 40 months and the median survival 39 months. Premenopausal women fared better than postmenopausal women with comparable response rates, duration of response and survival being 81.5%, 41 months, 56 months versus 50%, 20 months and 27 months. Of 16 premenopausal patients treated 7 achieved a complete response (CR) and, of these, 5 remained free of disease at 3 years. For these five individuals all treatment was then stopped. Disease recurred in two patients by five months but three remain disease-free after 43, 40 and 34 months, respectively without therapy. Toxicity was generally limited to heartburn and modest hair loss. This regimen appears to be more effective than those previously employed for metastatic breast cancer. However, comparative trials will be necessary to confirm its advantages.

PMID: 6687698 [PubMed - indexed for MEDLINE]




Breast Cancer Res Treat. 2010 Jun 29. [Epub ahead of print]Final results of a phase II study of nab-paclitaxel, bevacizumab, and gemcitabine as first-line therapy for patients with HER2-negative metastatic breast cancer.

Lobo C, Lopes G, Baez O, Castrellon A, Ferrell A, Higgins C, Hurley E, Hurley J, Reis I, Richman S, Seo P, Silva O, Slingerland J, Tukia K, Welsh C, Glück S.
Florida Cancer Specialists and Research Institute, Gainesville, FL, USA.


Stefan Glück
Email: SGluck@med.miami.edu
Abstract

In order to examine the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-P) in combination with bevacizumab (B) and gemcitabine (G) for the first-line treatment of patients with HER2-negative metastatic breast cancer (MBC). In this single-center, open-label phase II trial, patients with HER2-negative MBC received gemcitabine 1500 mg/m(2), nab-paclitaxel 150 mg/m(2), and bevacizumab 10 mg/kg (each administered intravenously) on days 1 and 15 of a 28-day cycle. The primary end point was progression free survival (PFS); secondary end points were overall response rate (ORR), complete (CR) and partial (PR) response rates, clinical benefit (ORR + stable disease), overall survival (OS), and safety. Thirty patients were enrolled. One patient was ineligible and was not included in analysis. Median PFS was 10.4 months (95% CI: 5.6-15.2 months). ORR was 75.9%, comprising eight (27.6%) CRs and 14 (48.3%) PRs; five patients had stable disease (SD) and two patients (6.9%) had progressive disease (PD) as their best response. The clinical benefit rate was 93.1% (27/29) in the overall group and 84.6% in the triple-negative cohort (11/13). The 18-month survival rate was 77.2% (95% CI: 51.1-90.5%). Eight (27.6%) patients experienced grade 3 or 4 toxicity: grade 4 neutropenic fever (n = 1) and grade 3 infection (n = 6), leukopenia, thrombocytopenia, peripheral neuropathy, seizure, shortness of breath, hematuria, and cardiac tamponade (one each). First-line therapy with nab-P, B, and G demonstrated a median PFS of 10.4 months and a 75.9% ORR with acceptable toxicity; this novel combination warrants investigation in a randomized study.

PMID: 20585851 [PubMed - as supplied by publisher]





Invest New Drugs. 2009 Apr;27(2):153-8. Epub 2008 Sep 5.
Phase I study of capecitabine in combination with cisplatin and irinotecan in patients with advanced solid malignancies.
Sayar H, Shen Z, Lee SJ, Royce M, Rabinowitz I, Lee F, Smith H, Eberhardt S, Maestas A, Lu H, Verschraegen C.
The University of Indiana Cancer Center, Indianapolis, IN, USA.


LINK

Abstract
PURPOSE: This phase I trial assessed the safety and the maximum tolerated dose of capecitabine given for 10 days prior to a combination of cisplatin and irinotecan in patients with advanced solid malignancies. It also evaluated the changes in cisplatin DNA adducts induced by capecitabine.
PATIENTS AND METHODS: Patients with refractory solid tumors who had not failed 5-fluorouracil (5-FU) analogs or topoisomerase I inhibitors were eligible. All cohorts of patients first received a 28-day cycle of cisplatin and irinotecan. Both drugs were given at a dose of 50 mg/m(2) intravenously on day 1, followed by irinotecan on days 8 and 15 at the same dose. The first cycle served as an internal control. Starting from the second cycle, patients received increasing doses per cohort of capecitabine from day 1 to 10 of each cycle, followed by cisplatin on day 11 and irinotecan on days 11, 18 and 25, both at same doses as the first cycle. Cycles were repeated every 38 days. The starting dose of capecitabine was 500 mg/m(2)/day which was escalated by 250 mg/m(2)/day in the subsequent cohort of patients to reach the maximum tolerated dose (MTD). Later, additional patients were treated at the MTD of capecitabine to further evaluate the safety, pharmacodynamics, and tumor response. Patients blood was tested for cisplatin-DNA adducts to determine the impact of capecitabine on cisplatin-based therapy.
RESULTS: Fifteen patients received at least 2 cycles of treatment. At 1,250 mg/m(2), two DLT of prolonged neutropenia of grade > or =3 were observed. The MTD for capecitabine was thus determined to be 1000 mg/m(2)/day. Fatigue and diarrhea of grade 1 or 2 were the most frequent toxicities at this dose level. No significant hematologic toxicity was observed at the MTD. Two complete and three partial remissions were observed. Four of the responders had received a platinum agent and/or 5-FU in the past.
CONCLUSIONS: A sequential treatment with capecitabine followed by cisplatin and irinotecan is well tolerated and demonstrates clinical activity in patients with advanced solid malignancies. The influence of capecitabine, if any, on the efficacy of the cisplatin-irinotecan combination is not related to a variation in cisplatin-DNA adducts.

PMID: 18773144 [PubMed - indexed for MEDLINE]


Site-dependent response to chemotherapy for carcinoma of the breast. 1985 CAF, CAMF good for lung and liver, mentions cooper regimen‏

FREE TEXT



Mol Cancer Ther. 2008 Jun;7(6):1669-79.
Synergistic effects of methylnaltrexone with 5-fluorouracil and bevacizumab on inhibition of vascular endothelial growth factor-induced angiogenesis.
Singleton PA, Garcia JG, Moss J.
Department of Medicine, University of Chicago, Chicago, Illinois, USA.


Abstract
Many patients with cancer receive combinations of drug treatments that include 5-fluorouracil (5-FU) and bevacizumab. Therapeutic doses of 5-FU are often associated with unwanted side effects, and bevacizumab is costly. Therefore, we explored potential agents that can reduce the therapeutic concentration of these drugs. Our data indicate that methylnaltrexone (MNTX), a peripheral antagonist of the mu-opioid receptor, exerts a synergistic effect with 5-FU and bevacizumab on inhibition of vascular endothelial growth factor (VEGF)-induced human pulmonary microvascular endothelial cell (EC) proliferation and migration, two key components in cancer-associated angiogenesis. MNTX inhibited EC proliferation with an IC(50) of approximately 100 nmol/L. Adding 100 nmol/L MNTX to EC shifted the IC(50) of 5-FU from approximately 5 micromol/L to approximately 7 nmol/L. Further, adding 50 ng/mL MNTX shifted the IC(50) of bevacizumab on inhibition of EC migration from approximately 25 to approximately 6 ng/mL. These synergistic effects were not observed with naltrexone, a tertiary mu-opioid receptor antagonist. On a mechanistic level, we observed that treatment of human EC with MNTX, but not naltrexone, increased receptor protein tyrosine phosphatase mu activity, which was independent of mu-opioid receptor expression. Silencing receptor protein tyrosine phosphatase mu expression (small interfering RNA) in human EC inhibited both synergy between MNTX and bevacizumab or 5-FU and increased VEGF-induced tyrosine phosphorylation of Src and p190 RhoGAP with enhanced activation of Akt and the actin cytoskeletal regulatory protein, RhoA, whereas silencing Src, Akt, or RhoA blocked VEGF-induced angiogenic events. Therefore, addition of MNTX could potentially lower the therapeutic doses of 5-FU and bevacizumab, which could improve index.

PMID: 18566238 [PubMed - indexed for MEDLINE]Free Article
























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Old 04-26-2011, 11:12 AM   #3
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Low-Dose Chemotherapy Protocol

Many conventional chemotherapy drugs, in addition to killing tumor cells, also fight angiogenesis. The anti-angiogenic effects of therapy may be masked and marginalized by the way it is usually administered. There are generally long breaks between drug administration that are necessary to allow the patient to recover from the harmful side effects of treatment.

When administering these drugs, the endothelial cells (involved in angiogenesis) are the first in the tumor to undergo cell death (apoptosis). However, this anti-angiogenic effect does not translate into a significant therapeutic benefit because the damage to the vasculature of the tumor can be largely repaired during the long rest and recovery periods between successive cycles of therapy.

The more frequent, lower-dose therapy can have an impressive anti-angiogenic and anti-tumor effects. Blood vessel cells are less likely than tumor cells to become resistant to chemotherapy, so if cancer cells become drug resistant, these medicines should still be able to shrink tumors by destroying their blood supply.

The main targets of dose-dense chemotherapy are presumed to be proliferating tumor cells. The main targets of low-dose chemotherapy are the endothelial cells of the growing vasculature of a tumor. In other words, chemotherapeutics can be used as anti-angiogenic agents.

Higher-dose standard chemotherapy treatment has been found to reduce the activity of the immune system's natural killer cells (white blood cells) by 96% (NCI). So if there are tumors growing elsewhere in the body and if the immune system helps to control tumor growth, then this method of chemotherapy could make things worse by allowing more rapid growth of the other tumors.

Whether chemotherapy is to be given and as well, what form it will take, are determined more by the idiosyncrasises and outpatient arrangements of the particular treatment center than by objective evidence of long-term efficacy. Long-term survival Platinum + Taxol combinations remain disappointing at higher-dose levels.

Conventional chemotherapy is given at high concentrations to force a drug or drug combination into poorly perfused areas of the tumor. The entire tumor is regarded as the target. This is not an ideal drug delivery.

The goal is to maximize drug delivery to the drug-accessible target receptors and minimize drug deposition elsewhere in the body. The target is not the entire tumor, it is just that part of the tumor that drug(s) can easily and freely reach after escaping from the tumor blood vessels. Just enough drug (s) is given to bind to the drug-accessible target receptors and kill the drug-accessible tumor. Over a long enough period of time, the drug (s) will eventually get to all the malignant cells.

Bottom line: more is not always better. How the role the drug delivery schedule plays in the disease control.

Sources:
Cell Function Analysis
Annals of Oncology (2002) Volume 13, Issue 1: pp. 12-15

http://cancerfocus.org/forum/showthread.php?t=3467

Last edited by gdpawel; 08-10-2011 at 09:19 PM.. Reason: spelling errors
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Old 04-26-2011, 12:38 PM   #4
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Re: Chemo Combinations/sequences with oomph

You probably meant to post this HERE or HERE

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Old 04-26-2011, 12:46 PM   #5
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Re: Low-Dose Chemotherapy Protocol

Greg and Rich -

Greg - Your wife's story is amazing! Rich 66 - many thanks for this great research.

Guess who's name comes back to mind? Dr. Block. Dr. Block adminsters low dose chemo timed to a person's biorythm's. Dr. Block takes Medicare. Hmm - maybe 2 years from now, I can give it a try.

My onc is great - really open minded, but probably wouldn't be into this. Is the low dose Fda approved? If so, that might approach may work for him.

Thanks!

- Kim
__________________
------------------------------
Dx Stage 3C 2005, triple +, tons of lymph nodes as well. FEC, surgery, TCH, rads, herceptin 1 year. And, Aromasin.
2007 - recurrence to medistinal lymph node, Abraxene and Herceptin - took it down 50%
2008 - on Arimidex/Herceptin - stable lymph node.
2009 - stable on Arimidex/Herceptin
2010 - lymph node progression and liver mets.
2010 - went on Gemzar, Navelbine, Herceptin - Navelbine and Herceptin took liver mets down. lymph node slightly progressed.
2010 - did Xeloda & Tykerb - MAJOR progression in liver in only 6 weeks.
Dec 2010 - present - Ixempra/Avastin/Herceptin/Fasoldex - regressing
June 2012 - chemo break
Sept 19, 2012 - start t-dm1. Chose this over going back on Ixempra.
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Old 04-26-2011, 04:21 PM   #6
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And talc pleurodesis

Kim

I should point out this additional information, because I really believe it had a significant contribution to her success. She received talc pleurodesis, which is a common treatment modality for patients with malignant pleural effusion, secondary to ovarian cancer, and breast and lung cancers. Pleural effusions indicate that the cancer has spread throughout the body. Talc, whether by poudrage or slurry, is the most effective pleurodesis agent available.

Talc causes tumor growth to slow down and actually decreases the tumor bulk, by stimulating healthy cells to produce the hormone endostatin. Talc is able to prevent the formation of blood vessels, thereby killing the tumor and choking off its growth. One of the reasons I have continued to do cancer research, because of the information I've found out years later.

http://news.ufl.edu/2007/06/06/talcum/

Block, I understand, also uses the cell-based functional profiling assays as a tool for some of their treatment protocols.

Greg
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Old 04-27-2011, 09:37 AM   #7
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Re: Chemo Combinations/sequences with oomph

Thanks Greg! I appreciate your update.

- Kim
__________________
------------------------------
Dx Stage 3C 2005, triple +, tons of lymph nodes as well. FEC, surgery, TCH, rads, herceptin 1 year. And, Aromasin.
2007 - recurrence to medistinal lymph node, Abraxene and Herceptin - took it down 50%
2008 - on Arimidex/Herceptin - stable lymph node.
2009 - stable on Arimidex/Herceptin
2010 - lymph node progression and liver mets.
2010 - went on Gemzar, Navelbine, Herceptin - Navelbine and Herceptin took liver mets down. lymph node slightly progressed.
2010 - did Xeloda & Tykerb - MAJOR progression in liver in only 6 weeks.
Dec 2010 - present - Ixempra/Avastin/Herceptin/Fasoldex - regressing
June 2012 - chemo break
Sept 19, 2012 - start t-dm1. Chose this over going back on Ixempra.
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