Thanks BarredOwl, I don't know is an honest answer. I wish more people used it. Hope it wasn't too much work.

I found this definition helpful:

https://www.cancer.gov/publications/dictionaries/c...

A measure of how often a particular event happens in one group compared to how often it happens in another group, over time. In cancer research, hazard ratios are often used in clinical trials to measure survival at any point in time in a group of patients who have been given a specific treatment compared to a control group given another treatment or a placebo. A hazard ratio of one means that there is no difference in survival between the two groups. A hazard ratio of greater than one or less than one means that survival was better in one of the groups.

The authors of the BIG 1-98 study state:

"We have undertaken an analysis of treatment adherence in the BIG 1-98 study to investigate its effect on disease-free survival (DFS)"

"The subsequent DFS of women who completed treatment and were disease free was compared according to compliance score."

Well, we don't know how often a DFS event happened in one group versus the other! Considering they went through all the trouble to conduct a retrospective analysis of patients who were disease free at the end of the study and assessed the effectiveness of compliance and persistence on DFS, it would have been helpful had they provided the actual number of patients who didn't have a recurrence taking the drug versus those who did. Not much can be gleaned from hazard ratios alone. I can't help but wonder that pertinent information is being withheld.

Numerous other publications have reported on the results of the BIG 1-98 trial (Filho (2015); Regan (2011); BIG 1-98 Collaborative Group (2009); Coates (2007); and BIG 1-98 Collaborative Group (2005)). I don't see the BIG 1-98 clinical trial investigators as witholding relevant information on these facts.

The purpose of this particular BIG 1-98 substudy was to assess the effects of persistence and compliance on disease-free survival and hazard ratios seem to be reasonably suited to their purpose. What they found is that those who adhere to the prescribed endocrine therapy (in terms of persistence and compliance as defined) can reap added benefit versus those who don't.

If a person with early stage invasive breast cancer has a pending treatment decision and is interested in how much they could potentially benefit from 5-years of initial endocrine therapy versus NO endocrine therapy, the results of this particular substudy are not of much help because that was not its purpose or focus and all of the patients were assigned to endocrine therapy.

By the way, they DID report on some 5-year DFS rates. See for example, Figure 2A-C (for regimens of greater than or equal to 36 months or less than 36 months). However, looking at this type of data is not very informative for the individual, because the DFS values are averages that were determined in groups of patients who had a good deal of variation in risk profile. (And again, they weren't comparing treatment to no treatment at all.) For example, the study population included patients with node-negative and with node-positive disease. About half had tumors less than 2 centimeters in size. Since benefit is known to be proportional to individual risk, patients should request more tailored estimates of their risk and potential benefit in their case from their medical oncologist (see my last post).

BarredOwl

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No clear evidence that most new cancer drugs extend or improve life

05 Oct 2017

The majority of cancer drugs approved in Europe between 2009 and 2013 entered the market without clear evidence that they improved survival or quality of life for patients, finds a study published by The BMJ.

Even where drugs did show survival gains over existing treatments, these were often marginal, the results show.

Many of the drugs were approved on the basis of indirect ('surrogate') measures that do not always reliably predict whether a patient will live longer or feel better, raising serious questions about the current standards of drug regulation.

The researchers, based at King's College London and the London School of Economics say: "When expensive drugs that lack clinically meaningful benefits are approved and paid for within publicly funded healthcare systems, individual patients can be harmed, important societal resources wasted, and the delivery of equitable and affordable care undermined."

The research team analysed reports on cancer approvals by the European Medicines Agency (EMA) from 2009 to 2013.

Of 68 cancer indications approved during this period, 57% (39) came onto the market on the basis of a surrogate endpoint and without evidence that they extended survival or improved the quality of patients' lives.

After a median of 5 years on the market, only an additional 8 drug indications had shown survival or quality of life gains.

Thus, out of 68 cancer indications approved by the EMA, and with a median 5 years follow-up, only 35 (51%) had shown a survival or quality of life gain over existing treatments or placebo.

For the remaining 33 (49%), uncertainty remains over whether the drugs extend survival or improve quality of life.

The researchers outline some study limitations which could have affected their results, but say their findings raise the possibility that regulatory evidence standards "are failing to incentivise drug development that best meets the needs of patients, clinicians, and healthcare systems."

Taken together, these facts paint a sobering picture, says Vinay Prasad, Assistant Professor at Oregon Health & Science University in a linked editorial.

He calls for "rigorous testing against the best standard of care in randomised trials powered to rule in or rule out a clinically meaningful difference in patient centred outcomes in a representative population" and says "the use of uncontrolled study designs or surrogate endpoints should be the exception not the rule."

He adds: "The expense and toxicity of cancer drugs means we have an obligation to expose patients to treatment only when they can reasonably expect an improvement in survival or quality of life." These findings suggest "we may be falling far short of this important benchmark."

This study comes at a time when European governments are starting to seriously challenge the high cost of drugs, says Dr Deborah Cohen, Associate Editor at The BMJ, in an accompanying feature.

She points to examples of methodological problems with trials that EMA has either failed to identify or overlooked, including trial design, conduct, analysis and reporting.

"The fact that so many of the new drugs on the market lack good evidence that they improve patient outcomes puts governments in a difficult position when it comes to deciding which treatments to fund," she writes. "But regulatory sanctioning of a comparator that lacks robust evidence of efficacy, means the cycle of weak evidence and uncertainty continues."

In a patient commentary, Emma Robertson says: "It's clear to me and thousands of other patients like me that our current research and development model has failed."

Emma is leader of Just Treatment, a patient led campaign with no ties to the pharmaceutical industry, which is calling for a new system that rewards and promotes innovation, so that more effective and accessible cancer medicines are brought within reach.

Source: The BMJ

BMJ 2017;359:j4585 doi: 10.1136/bmj.j4585 (Published 2017 October 05) Page 1 of 1

Editor's Choice

EDITOR'S CHOICE

What you need to know about cancer drugs

http://www.bmj.com/content/bmj/359/bmj.j4585.full.pdf

Bosombuddy101, did you see this? There are contacts at the bottom of the page. Maybe you could just email them to get an answer to your question?

Interpreting breast international group (BIG) 1-98: a randomized, double-blind, phase III trial comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive, early breast cancer | Breast Cancer Research | Full Text

https://breast-cancer-research.biomedcentral.com/articles/10.1186/bcr2837

Edited to correct link

ok, I fixed it and tried it, it works

FDA approval of most drugs is based on "registrational" trials such as BIG 1-98 sponsored by the drug manufacturer (for obvious reasons). I explained above why Chirgwin used hazard ratios.

There is a large body of scientific medical literature regarding Tamoxifen and for each of the three Aromatase Inhibitors ("AI") that demonstrates the clinical benefit of five years of endocrine therapy. Tamoxifen improves outcomes over placebo, reducing mortality, distant recurrence, locoregional recurrence and new disease (ipsilateral, contralateral). This EBCTCG (2011) meta-analysis included individual patient data from twenty (20) clinical trials including 21,457 patients in early breast cancer of around 5 years of tamoxifen versus no adjuvant tamoxifen. The AIs have been demonstrated to have comparable or slightly better activity than Tamoxifen (see e.g., this meta-analysis Dowsett (2010)).

These studies establish the relative risk reduction benefits of Tamoxifen relative to no endocrine therapy. Benefit has been shown to be proportional to individual risk. This allows Medical Oncologists to provide more individualized estimates of potential absolute benefit, based on estimates of individual recurrence risk.

Here are a couple of publications from BIG 1-98:

Regan (2011): "Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up"

http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70270-4/fulltext

Filho (2015): "Relative Effectiveness of Letrozole Compared With Tamoxifen for Patients With Lobular Carcinoma in the BIG 1-98 Trial"

http://ascopubs.org/doi/full/10.1200/jco.2015.60.8133

BIG 1-98 was not a placebo-controlled trial, because of ethical constraints. Instead, Letrozole (5 years) or certain switch regimens were compared to Tamoxifen (5 years). Therefore, the benefit of an AI over Tamoxifen is over and above the benefit that Tamoxifen provides.

My MO presented me with a graphic that showed the risk of serious SE's (uterine cancer, stroke, blood clots, cataracts) occurring while on Tamoxifen vs the general public. The risk is real but very small. Still scary.

The incidence of annoying and sometimes QOL ruining SE's seems to be pretty high - hence the number of women who stop taking it. I've had so many SE's to so many things I've taken that I was fully expecting the worst.

I had actually pretty much decided against it, rationalizing that my cancer responded extremely well to treatment and I had a mastectomy. I felt like my odds were pretty good. The truth is - nowhere do they differentiate between type of surgery or chemo response when they give statistics. My personal risk is probably better than the 14% or so listed. But Tamoxifen will cut that in half.

I figured I'd try it anyway, thinking I could quit if it got too bad. I had HORRIBLE muscle spasms in my legs every night for about 3 weeks and was ready to throw in the towel. And then they magically disappeared. I had already tried a bunch of recommendations that didn't work. Maybe it took that amount of time for my body to adjust.

Anyway, I don't think that I have any SE's now. My whole body and mind are a mess in one way or another from the brunt of the past year so maybe I just don't know the difference. But I'll do this for now anyway because I really don't want to deal with this mess again.

I wish everyone luck - and peace in their decisions.

No - it's actually warmer now than it was! And I've been well hydrated all along and taking Magnesium, Calcium, and B complex vitamins along with a multivitamin. I've had a history of leg cramps during pregnancy and off and on at other times for similar causes to what you mentioned. This was extreme spasms that would occur every night, multiple times, for minutes on end - despite activity level, stretching, bananas, etc.

I did find some studies that linked Tamoxifen's estrogen effects to a decrease of blood flow, especially at night. I was considering requesting a medication that they give for intermittent caudication. You know - those another med at it!

Just so, so glad it's better

Bosombuddy...unfortunatley there are many people on the Stage 4 forum who "did everything" and now are dealing with Stage 4 BC. There are just no guarantees. Of course there are things we can do to lower our chances of recurring. We need to make our own informed decisions about treatment options. Good luck to all navigating this complicated disease.