navelbine and cardio-toxicity

[al from Canada]

Dear friends,
Check-out the underlined / bolded sentance I highlighted near the end of the abstract. Is vinorelbine an anthracyline?? I thought I heard this at SABCS but it didn't register. Reading this brought it back, this time with a big question mark!
Regards,
Al

A phase II study on metastatic breast cancer patients treated with weekly vinorelbine with or without trastuzumab according to HER2 expression: changing the natural history of HER2-positive disease.Ann Oncol. 2006 Jan 12;

Papaldo P (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Papaldo+P%22%5BAuthor%5D), Fabi A (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Fabi+A%22%5BAuthor%5D), Ferretti G (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Ferretti+G%22%5BAuthor%5D), Mottolese M (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Mottolese+M%22%5BAuthor%5D), Cianciulli AM (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Cianciulli+AM%22%5BAuthor%5D), Di Cocco B (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Di+Cocco+B%22%5BAuthor%5D), Pino MS (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Pino+MS%22%5BAuthor%5D), Carlini P (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Carlini+P%22%5BAuthor%5D), Di Cosimo S (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Di+Cosimo+S%22%5BAuthor%5D), Sacchi I (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Sacchi+I%22%5BAuthor%5D), Sperduti I (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Sperduti+I%22%5BAuthor%5D), Nardoni C (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Nardoni+C%22%5BAuthor%5D), Cognetti F (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Cognetti+F%22%5BAuthor%5D).

Division of Medical Oncology A, Regina Elena Cancer Institute, Rome, Italy.

Purpose: To observe whether in pretreated metastatic breast cancer patients with HER2-positive disease vinorelbine plus trastuzumab can produce different overall response rate (ORR), time to progression (TTP), and overall survival (OS) from women with HER2-negative tumors treated with vinorelbine alone. METHODS: Between June 2000 and January 2004, 68 consecutive women were enrolled: 33 patients received vinorelbine (V) alone, while 35 patients were given trastuzumab plus vinorelbine (T+V) according to HER2 expression determined by immunohistochemistry. In tumors scored +2, HER2 gene amplification was determined by fluorescence in situ hybridization. RESULTS: In patients treated with V (HER2-negative tumors) the ORR was 27.3%, while in those given T+V (HER2 positive tumors) the ORR was 51.4%. The median duration of response was 8 months for women treated with V and 10 months for those who received T+V. Patients given T+V had a longer TTP (9 months) and OS (27 months) than those receiving V alone (6 months and 22 months respectively). Toxicity was mild in both groups. Concerning cardiotoxicity in T+V group, 7 patients (20%) had left ventricular systolic disfunction. CONCLUSION: Our data suggest that trastuzumab can change the natural history of HER2-positive metastatic breast cancer. In fact, when treated with trastuzumab, women with HER2-positive disease had better prognosis than patients with HER2-negative tumors. Conducting a formal phase III trial comparing vinorelbine alone vs vinorelbine plus trastuzumab in HER2-positive metastatic breast cancer women could be debatable.

[Lani]

What a stupid study--they compared apples with oranges!!!!Her+ breast cancer is one entity, her2- is another. They have different genes expressed/repressed, different behaviors, respond to different treatments.

It does point out, although it is poorly planned and executed, what we are happily finding out. That in the age of Herceptin, being her2+ may no longer be such a terrible disadvantage and is turning out to be an advantage--targetted therapy, vaccine therapies, targetted imaging, good serum marker test...

What we can now see, is that the clinical researchers in the first and second-world countries of the world will now be unable (except perhaps in third world countries) to do trials for patients who are her2+ and metastatic without offering both arms herceptin as it has been shown to be beneficial and treating someone without it would be immoral. This is how progress gets slowed down. Should they develop further a multiERBB antibody agent like pertuzumab(which gets 3 erbb receptors I believe) or one which could engage all 4(may or may not be necessary as her2 has no known natural ligand) they can only test it with Herceptin. To give it without would deny the patient the best known treatment

Al, concerning the 20% figure
1) this was in a small number of patients so statistics can easily be "warped"

2) they may have received a lot of anthracyclines in their "pretreatment" ie, adjuvant treatment

3) they may have been old with preexisting heart problems

4) they may not have had the proper baseline muga before starting or not been followed closely enough and disqualified quickly enough

5) they may have not had the most up-to-date radiation therapy and had left sided breast cancer in which case the double/triple insult of anthracyclines(or other cardiotoxic chemos), radiation and herceptin caused their problems.

6) they may have had excitable Italian husbands that stressed them out!!!!

These are but a few of the possibilities. Let's see if we can get the whole article!

Lani

[Lolly]

I found this very interesting site which describes the mechanism of action for each class of anti-cancer agent. I thought you all might be intrigued also:

Anti-Tumor Agents by Mechanisms of Action

http://www.sigmaaldrich.com/Area_of_Interest/Life_Science/Cancer_Research/Key_Resources/Mechanisms_of_Action.html

[Lolly]

...a bit more info gleaned:

"...Vinorelbine belongs to a class of chemotherapy drugs called plant alkaloids. Plant alkaloids are made from plants. The vinca alkaloids are made from the periwinkle plant (catharanthus rosea). The taxanes are made from the bark of the Pacific Yew tree (taxus). The vinca alkaloids and taxanes are also known as antimicrotubule agents. The podophyllotoxins are derived from the May apple plant. Camptothecan analogs are derived from the Asian "Happy Tree" (Camptotheca acuminata). Podophyllotoxins and camptothecan analogs are also known as topoisomerase inhibitors. The plant alkaloids are cell-cycle specific. This means they attack the cells during various phases of division.

Vinca alkaloids: Vincristine, Vinblastine and Vinorelbine
Taxanes: Paclitaxel and Docetaxel
Podophyllotoxins: Etoposide and Tenisopide
Camptothecan analogs: Irinotecan and Topotecan
Antimicrotubule agents (such as vinorelbine), inhibit the microtubule structures within the cell. Microtubules are part of the cell's apparatus for dividing and replicating itself. Inhibition of these structures ultimately results in cell death..."

[Lolly]

OK, last link, I promise!(along with an exercpt):

Cardiac Toxicity
http://patient.cancerconsultants.com/supportive_treatment.aspx?id=23145

"...There are specific classes of drugs, such as the anthracyclines (doxorubicin, daunomycin, epirubicin, mitoxantrone and idarubicin), that are known to cause damage to the muscle cells of the heart. The anthracyclines are also given with other drugs, such as alkylating agents and vinca alkaloids, which can contribute to heart damage. In addition, radiation therapy to the chest wall or area around the heart can affect the blood vessels supplying the heart, leading to a myocardial infarction or “heart attack”. Since many patients, especially with lymphoma or breast cancer, receive both anthracycline-based chemotherapy and radiation therapy, there may be a cumulative effect on the heart. The following is a brief outline of the major drugs that have been associated with long term complications to the heart..."

Lolly here; And lastly, I think the heart damage experienced by the study group on Herceptin/Navelbine could well have been as a result of the Herceptin, and especially in combo with Navelbine.

[Unregistered]

I skimmed through Lolly's list of agents.

I saw that curcumin is listed as an EGFR (HER 1) inhibitor. Somebody previously was asking about natural EGRF inhibitors.

There is also a NCBI link on articles of interest givgin the full low down on treatment regeimes, side effects etc.

But as usual please check it out for youeself I have not done an in depth on it.


RB