Chemo Combinations/sequences with oomph

[Rich66]

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

[gdpawel]

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

[radiant]

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

[gdpawel]

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

[radiant]

Thanks Greg! I appreciate your update.

- Kim