Premature @ MindSay

A very large clinical trial (~10,000 women) is underway to assess the usefulness of the Oncotype Dx gene profile for selecting treatment for early stage estrogen receptor positive breast cancer: the TAILORx Trial.  The trial sponsors will ask women with breast cancer to undergo Oncotype Dx testing (for which they will be billed $3650) and then assign them to three risk groups based on their recurrence score. (The groups are defined using different cut-off’s for this trial than those used for the study done on the NSABP B-20 tumors.)  Women in the low risk score group will get hormonal treatment (tamoxifen or one of the newer “aromatase inhibitor” class of drugs). Women in the high risk group will get chemotherapy and hormone therapy. The women in the intermediate group will be randomly assigned to receive either hormone treatment alone or a combination of hormone and chemotherapy.

A least four concerns make this trial seem premature. First, the chemotherapeutic "validation" of Oncotype Dx is based on one small, old chemotherapy trial. Second, TAILORx does not incorporate many other old and new prognostic indicators that might trump Oncotype Dx in some circumstances. Third, not enough information exists about how the Oncotype Dx score might interact in a confounding way with specific hormone treatments, chemotherapy drugs, and regimens. Finally, far too many non-random, non-blinded choices are afforded to patients and physicians in TAILORx to make for decent "science".

TAILORx is based on a retrospective analysis of a small, non-random sample of assays performed on preserved tissue. The ability to use this old material to obtain reproducible gene profiles is an amazing technological feat, to be sure. But only 651 of about 2300 patient results were available. The chemotherapy used in the NSABP B-20 dates to the 1970's. Substantial evidence supports a conclusion that these regimens improve prognosis for many patients. But two of the agents (methothrexate and 5-fu) are not often employed today. The third agent, cytoxan, has lost popularity over concerns that it may lead to late complications like second malignancies. Meta-analysis of the many thousands of patients treated with chemotherapy indicates that the B-20 drugs are not as effective as newer drugs like the taxols and adriamyin.

So inspite of the fact that the paper describing the results for the 651 patients uses the word "prospective" five times, it is actually a retrospective survey, not a clinical trial. This might matter for a woman who is enrolled in TAILORx because she cannot be sure that the Oncoype Dx group studied really is representative of the group she is in. And remember that much of the power of the argument for Oncotype Dx is contained in the one subgroup that contained only 47 patients.

A second concern revolves around the lack of  consideration of many other older and newer prognostic variables when deciding whether a patient falls into "Group 2" (the intermediate risk group) as defined here:

Group 2 (Primary study group; ODRS 11-25): Patients are stratified according to tumor size (≤ 2.0 cm vs ≥ 2.1 cm), menopausal status (postmenopausal vs premenopausal vs perimenopausal), planned chemotherapy (taxane-containing [i.e., paclitaxel, docetaxel] vs nontaxane-containing), and planned radiotherapy (whole breast with no boost planned vs whole breast with boost planned vs partial breast irradiation planned vs no planned radiation therapy [for patients who have had a mastectomy]). Patients are then randomized to receive either hormonal therapy alone or combination chemotherapy and hormonal therapy.

For example, tumor size, tumor dna ploidy, quantitative level of estrogen receptor, tumor lymphovascular invasion, per cent of dividing cells ("s phase"), Ki 67 expression and many other features and meaurements have been used to stratify patients for risk of treatment failure. (Some of these features can make a woman with a very small tumor (<1 cm) eligible for inclusion in the trial, an acknowledgement of their possible importance). And of course, clinical features on presentation may predict risk of failure. Mammographically discovered cancers may have a different prognosis compared to those discovered by the patient feeling a mass, for example.

Under TAILORx rules, a 48 year old woman with a palpable 4.9 cm cancer that is high grade with lymphatic invasion, weakly estrogen receptor positive, Ki 67 expression and an S phase of 20 and a Oncotype Dx score of 23 (intermediate risk) could be randomly assigned to tamoxifen alone.

Some will argue that the hypothetical patient described above would be unlikely to have an Oncotype Dx score as low as 23. (The B-20 Oncotype Dx analysis used 18 to 31 to define the intermediate risk group. The range was changed to 11-25 for TAILORx, possibly because her2+ patients are excluded - more on this below.) This is probably true, since the Oncotype Dx score does correlate to some extent with many "traditional" indicators. However, if the above hypothetical patient exists, few cancer physicians would advise tamoxifen alone. This would result in one of two outcomes for our hypothetical patient.

First, the woman would not likely be offered the TAILORx trial. Or, if she were offered the trial and the randomization resulted in tamoxifen alone, she would be advised to withdraw from the trial and receive chemotherapy. Either way, the results from TAILORx will be compromised. If patients on the "edges" of the "groups" are manipulated to get the "right" treatment, the trial results will be of little use, because the "borderline" cases are the very ones that present the most difficult decisions, and the Will Rogers phenomenon will be in play to distort the results.

A third concern that may make TAILORx premature is the paucity of information about how the Oncotype Dx predictive power might be affected by the choice of hormone and chemotherapy agents. The TAILORx protocol allows each physician to choose a chemotherapy regimen and/or hormone agent. Some might still choose the B-20 CMF and tamoxifen regimen for patients perceived to be at lower risk (within the intermediate group), while others might choose "dose dense" taxol containing aggressive treatment for a patient like the hypothetical one described above. There are many reasons why this may lead to errors.

The gene for glutathione S-transferase (GST) GSTM1 is one of the 16 predictor genes in Oncotype Dx. The presence of this gene tends to improve prognosis. The problem is that this gene also affects the metabolism of some cancer drugs. Anticancer drugs that have been shown to be substrates for GSTs are, for example, chlorambucil, melphalan, cytoxan metabolites, and steroids.  Indirect evidence for a role of GSTs in modulating drug effects through deactivation of drug-generated hydroperoxides or other reactive oxygene species exists for adriamycin, mitomycin C, carboplatin, and cisplatin, but not taxol. Some have postulated for other malignancies like acute leukemia in children that gstm1 confers a favorable prognosis because it changes chemotherapy metabolism. Oncotype Dx does not identify which patients have one copy of GSTM1 (a null polymorphism) and which have two copies. Remember B-20 chemotherapy often included cytoxan but never taxol. 

Another gene in Oncotype Dx is her2. Patients with tumors that express her2 are exluded from TAILORx. This gene is a prototype marker for chemotherapy selection since the drug Herceptin works very well when it is expressed and not at all if it isn't. B-20 contained a number of her2 positive patients and herceptin was not available in that era. So the Oncotype Dx used in TAILORx is a different one than the one tenuously "validated" in B-20. If the her2 gene is a totally independent predictor, the change might not matter. But her2 does interact with other cancer genes, for example the Src family. Src is a family of proto-oncogenic tyrosine kinases originally discovered by J. Michael Bishop and Harold E. Varmus, for which they won the Nobel Prize.

Bag1 is another gene in Oncotype Dx and it interacts with the estrogen receptor (alpa) mechanisms which can control cancer growth. Does it interact with tamoxifen (studied in B-20) the same way as the aromatase inhibitors included in TAILORx (but not in B-20)? BAG1 seems to predict respone to tamoxifen but how it predicts benefits from other hormones or chemotherapy is less clear.

TAILORx is constructed on a tenuous foundation based on a very small number of observations (remember the 47 patieint subgroup) and on many exrapolations based on assumptions. Some of these may seem niggling, such as the fact that B-20 used age 70 and tumor size 4cm as cut offs and TAILORx uses 75 and 5 cm. Yet B-20 found a suggestion that age and chemotherapy effectivenes interact and that tumor size affects prognosis.

And, one more thing: how can "partial breast radiation" be allowed in a non-random way? This would imply that partial breast radiation has become an acceptable "standard of care". Where are the appropriately powered randomized trials that support this implication? Don't be fooled into thinking that an analysis of this non-randomly assigned "stratification" can answer any useful question.

Stratification (i.e., prospective randomization within smaller, rigidly predefined clinical subroups) is often employed in clinical trials (though purists might argue that this is unnecessary in trials with a large number of outcome events).  But TAILORx is not stratified by rigidly predefined criteria. Rather it will permit thousands of patients and physicians to choose among a rich buffet of treatment options related to local therapy ((type of node sampling (any type among many permitted), type of mastectomy (any type among many), lumpectomy (any type among many), radiation (type of radiation, partial/whole radiation), chemotherapy (literally thousands of combinations and permutations of drugs and doses) and hormones (serms and aromatase inhibitors).)

Stratification might make sense if it were based on close to totally objective (not really ever possible in the real world) and independent classifications. Stratification makes no sense if it based on thousands of differing views and biases related to the risks and benefits of a multitude of differing therapies. Those decisions will be largely based on the very risk assessment conderations that the TAILORx trial is supposed to answer.

"Although technological advances will further improve our understanding of breast cancer and will contribute to tailoring treatment to the individual patient, our experience with adjuvant CMF over 30 years confirms that the effects of such a regimen are long lasting and may benefit patients with favourable and unfavourable prognostic indicators, at the cost of minimal long term sequelae." This is how Dr. Bonadonna himself described in 2005 (emphasis added) results from the chemotherapy regimen that is still often called "Bonadonna CMF". "Tailoring treatment" is the holy grail but TAILORx is designed too clumbsily to trump 30 years of better designed clinical trials.

Monks from the Order of the Brothers of the Statistic will study the scripture that flows from TAILORx and will be able to devine all the potential biases and confounders by utililizing probabilistic testing based on dubious underpinnigs that may well result in some very "significant" and small "p" numbers. Cultists who worship at that particular altar of "evidence based" medicine will travel about with their power point slides of life table graphs and p values carried to the fourth decimal point, Genomic Health will turn a profit for the first time and its shares will skyrocket, and another level of the temple known to heretics as the "House of Cards" will have been constructed.

Or maybe the results will look so powerful that even a skeptic like me will be convinced (or fooled).

TAILORx may be another example of the technological imperative in action. TAILORx reflects the fervent need of patients and doctors for a simple "black box" method for making difficult choices. The admonition of H.L. Mencken bears remembering: "For every complex problem, there is a solution that is simple, neat, and wrong."

I'm nine weeks pregnant today. It doesn't sound a lot - um, because it isn't - but it is sort of a big deal to me, because the last few weeks have dragged on sooo much. Nine weeks. Shame it isn't nine months. But nine weeks to me is close enough to call a quarter of the way there. And that's good to know!

Not that I don't want to be pregnant - believe me, I do. I went through that last week, where I didn't want to be... but I think that is safely under the carpet. I'm just impatient. I found out at a really early stage (never known that soon before) and because I haven't felt pregnant, and I've been so worried about everything, the last few weeks have been slow and hard.

I'm still worried though, but not quite as much. Not being able to hear the baby's heartbeat at the first ultrasound really took its toll on me - I didn't just think we'd lost the baby, I knew we had - but of course, we didn't, the little peanut's heartbeat showed up straight away the next day. And that really helped put my mind at rest and helped me stop worrying so much.

I am not so much worried about miscarrying now.. although I know it is still possible (I miscarried at seventeen weeks before) but for some reason I'm not worrying about that as much as I have been before. I am most worried now about going into labour early again. I am really scared about having another baby in NICU. Unless you've been through that yourself, you cannot imagine how hard it is, how emotionally - and even physically - draining it is. I have been through that twice already, with Riley and Taylor, and Amelia was there for 9 weeks, but that is two times way too many.

I know an early baby doesn't necessarily mean an unhealthy baby.. Ben was five weeks early and he was perfect in every way; although a little on the small side (4lbs 12oz) he was able to come straight home. And to look at Mia now you'd never know that she was so tiny and fragile as a baby (hell the word fragile doesn't come anywhere near that child.. haha), but that still doesn't make the experience of having a premature baby any less difficult.

I suppose most of these worries are fuelled by all the dreams I've been having to do with the baby. The ones where she/he dies, or I kill it (that was the worst) seem to have stopped (touch wood), but now I'm having a lot where she/he is premature and really sick.

I know I have a long way to go anyway, and I really shouldn't worry this early on, but hey worrying is what I do- I can't help that! I can just hope, and hope really hard, that everything is going to go well this time.

Oh, and everyone needs to wager a bet on whether I'm having a girl or boy :)

Some time in January 2002, I found out I was pregnant. I had been back with Joshua for over a year, but I was still living at home with my mum. The first step was to become a proper family unit, and maybe a month after learning the news, we rented a flat at moved in together.

Being my third baby at a young age, it took a lot to get used to the idea of being pregnant. Of course I was shocked to find out; we both were… but we slowly adjusted to the idea. It took a lot to get used to having a third baby, and just as I was building up for the idea, I realised I was way bigger than I should have been for how far along I was. I joked with a friend online about how I might be having twins again.

And no joke, maybe a week after that, I found out I actually was having twins. Again.

Of course that, again, took a whole repeated process of having to come to terms with the news. People were in disbelief that I was having a second set of twins – people still find it hard to believe that I had two sets of twins – but believe me, no-one was as shocked as me.

I was going to have four babies. Four babies, aged two and under. Kelsey and Ally had only just turned two at this point. I was due in August, and they’d still be only 2 and a half when they were born. When you’re only sixteen yourself, it’s one hell of a scary prospect. I never did come to terms with the idea.

When I was twenty four weeks pregnant, I woke up one morning to having really bad cramping. I thought maybe I just needed to go to the toilet, but when I went, I saw that I was losing a lot of blood. I instantly started panicking, and woke up Josh, and five minutes late we were on our way to the hospital.

When we got there, I was rushed straight into A&E where I was told I was in the onset of extremely premature labour. I was admitted, and luckily they managed to control labour and stopped it. I was given drugs to mature the babies’ lungs just in case, and spent the night in hospital.

I was released the day after, but to be on complete bed rest at home. I’m not the sort of person who can deal with being just laid in bed constantly – I was even less the sort of person at that time. Then, I couldn’t see the consequences of not taking the doctor’s orders seriously. If only I did.

I did try to take it easy, but I wasn’t often laid down in bed. When I was in bed I was sat up watching TV or reading, which defeated the object. Only a few days after I’d got out of the hospital, I saw my father for the first time in around eight years. Not that it was a particularly traumatic ordeal, but it couldn’t have helped the stress factor all too much.

Only a week later after being sent home from the hospital, I had a repeat of what happened before; only worse. I was losing a vast amount of blood, as well as cramping and contractions worse than before. I knew instantly it was my fault for not listening to the doctor more carefully. I knew this time they wouldn’t be able to do anything, and on the way to the hospital I prepared for my third and fourth daughters to be born.

I was right; there was nothing that they could do to stop labour. If my babies weren’t delivered right there and then, all three of us could be in danger. Both the girls heart rates had slowed right down and were erratic; it had to be that I was rushed in for an emergency c-section right there and then or they definitely wouldn’t make it.

Twenty-three weeks is the viable mark. If a baby is born at twenty three weeks, there is just the smallest chance a miracle might happen and they might survive through their first few weeks. My girls were about to be born only two weeks past that “viable” point. It was all I could do to cling to some little hope that the small amount of steroids they were given a week earlier would help, and that the doctors were miracle workers. Which of course, they weren’t.

I don’t remember anything about their delivery. I was knocked out cold before I’d even got into the theatre. Josh wasn’t allowed in there. Who knows what was going through his mind at the time, but it didn’t make any difference to me since I had no idea what was happening.

Riley Madison was born at 7:23am on the fifth of May, 2002. Taylor Mackenzie was born at 7:25am. Both of them weighed 1lb 10oz. Barely the size of your hand. Both managed to take a breath on their own after being born, but of course were whisked straight away to get the help they needed.

Of course, I didn’t know any of this until I came round, which was a good many hours later. I woke up screaming that I wanted to see my babies – I didn’t know anything. I didn’t know if they’d made it or anything. A nurse told me eventually that they were okay, and they’d been taken to the special care baby unit. I say eventually; it was probably only five minutes after I’d come round but I was hysterical, and it seemed like forever.

I was still hysterical after knowing they were okay. Because of course they weren’t okay. They were born fifteen weeks early, how could they be okay?! I wanted to see them. They were so far away from me. I hadn’t seen them. Not even a glimpse. I couldn’t even imagine what they might look like.

For almost two days, all I got to see of them was a Polaroid picture of each of them. Labelled “baby A” and “baby B”. Riley was baby A. I could barely make out their tiny faces, but they were both so small. About the size of the doctor’s hand which you could see in the photo. Their tiny bodies were covered in tubes and tapes, and I was literally petrified of going to see them the first time I did.

It was Monday night, after they were born on Sunday morning. When I saw them both lying there in their incubators, just about every emotion you can imagine flooded through me. Love, fear, anger, happiness, sadness… the list goes on. I was shaking so much when I first saw them. I couldn’t touch them for hours. I just sat and stared at them both, lying there helpless. They looked tiny in the photograph, but that was nothing compared to how tiny they actually were in real life. That first day I saw them, I sat staring at them both for endless hours, sobbing to myself. But they were both so beautiful. So very beautiful. Incredibly fragile; I managed to briefly stroke their hands after a few hours that first night but had to draw away straight away. It was a good couple of days before I realised I was okay to touch them and I wouldn’t hurt them. They both had heads full of dark hair. So much hair, in fact. Brilliantly black, and they were beautiful. They weren’t identical, but they looked very alike.

I was discharged from the hospital five or six days after they were born. I still spent every possible moment there though, by the sides of their incubators. I’d talk to them, hold their hands, stroke their hair… just gaze at them for all the hours I possibly could; soaking in as many memories as possible, because deep down, I think I knew I’d need them later.

I felt like I was neglecting Kelsey and Alliza, having to spend so much time at the hospital. They were only two; they didn’t understand in much detail why we had to leave them with their Nana. After about a week, we took them both up to visit their new little sisters, who they’d only heard stories about. Though they were both so young, they understood so well about Riley and Taylor. They knew they were their little sisters. They knew they were both very poorly. But they loved them. They’d ask about them every day when we came home, and hand us their favourite cuddly toys to go and take for them to have.

Riley was the weakest twin from the beginning. Though only by a matter of grams, she was the smallest – she looked the smallest, even if there wasn’t much between them in their weight. She was always the same. Critical but stable. They both were. With Riley, there was never a point we were told she was doing really well, but she did show improvement. In her first two weeks, she had gained a little weight. And because they’d both done well in their first week or so, it was looking optimistic – even secretly – that maybe they were going to be fine. Maybe the doctors were miracle workers.

The evening of the 19th May – they’d were two weeks old. I’d only seen them that morning. They were doing okay… or I’d thought so. I got a phone call about 9pm that night from the doctor in the Special Care Baby Unit. You know if you hear his voice on the end of your telephone line, he is going to be delivering bad news. I remember that night so vividly. Just before we received the phone call, I’d been chatting to friends about how good both my babies seemed to be doing. I remember getting the phone and just dropping everything and running out of the door. Kelsey and Ally were asleep in bed, but we had to leave them on their own while my mum came round to watch them.

On the phone, he’d said Riley had taken a turn for the worst.

In the car, I sobbed my eyes out. I cried all the way through the hospital corridors as we rushed to the SCBU. I sobbed as we saw the doctor waiting for us outside their intensive care unit. I sobbed as he explained to me what had happened to Riley. I couldn’t take any of it in. His words were just mixed with my tears, and none of it I could believe. It wasn’t happening; it was just a bad dream. I’d wake up in my own bed in the morning, and head down to the hospital where they’d both be. They’d be doing great; they’d be doing better than ever.

But I knew what was happening was the reality, and the tomorrow I hoped for would never come.

Riley had taken a turn for the worst. They’d found she had septicaemia in her tiny body – a blood infection. She was too weak and the infection was too severe. We’d lost her.

I ran away. I got up and I ran away. I ran down the corridor we’d come along, and out of the building. I collapsed against a wall outside and sobbed so hard I could barely breathe. I never saw my baby girl again. I didn’t cradle her in my arms. I’d never held her; not in life nor in death. Having never held her while she was alive, I didn’t want the first time to be when it was already too late.

I still had to be strong. Taylor still kept fighting, and we had to be strong for her. Kelsey and Ally needed us to be strong for them too. The very next day I still visited the hospital like I usually would. I focused on Taylor, and not the empty incubator that laid beside her. Taylor was getting much stronger. From the day before to then, I could see a vast difference in her. I felt that Riley was keeping her going. Her own body wasn’t strong enough to save herself, but her spirit had the power to help her sister.

It was that day I got to hold her for the first time. It felt wonderful to finally be able to cradle my little girl. I cried of both happiness and sadness. Happy to finally feel her close to me; sad there was only one baby, and not two. That there would only ever be one baby that I’d held and not two. It was still so raw, and I had nowhere near begun to realise that I’d just lost my daughter.

Her funeral was ten days later. If I had my own way, I wouldn’t have gone. I couldn’t face going. It was really small. I didn’t want a lot of people there. It was only our immediate family. It was only then that it hit me one of my baby girls was dead.

Up until then, Taylor had been doing amazingly well. She’d put on quite a lot of weight, and she looked a lot healthier than she had only three weeks or so before. I was told that if she continued to do so well, she’d be able to come home in maybe a month.

That was the greatest news I could have heard, to know that it seemed a miracle had happened, and my baby was pulling through. It was such a prospect, to ever imagine that I’d get to bring her home. Home. Out of the hospital. I couldn’t have all four of my girls together, but to know that I could have three of them together at home, healthy and happy, was an amazing thought. And it would be reality.

It should have been reality, but it wasn’t.

Only a couple of days after being told we could look forward to bringing her home, Taylor too passed away to join her sister. Just a regular infection that would bear hardly any effect on someone else; her little body just couldn’t fight it.

Barely more than a week after Riley’s funeral, Taylor was buried right next to her sister. At least they were together again. At least.

The one time Kelsey and Ally visited them in the hospital was the only time they ever met their little sisters. I don’t know if they remember seeing them or not. That was the only time we had our four baby girls together, and I’ll cherish that memory forever. I don’t like bringing it up with Kelsey and Ally – well, I don’t like bringing it up with anyone. I know they remember Riley and Taylor. I don’t know if that’s only through photographs and things they’ve been told, probably from my mum. They have occasionally asked questions about them, and one day I will explain everything to them, and take them to visit their graves, but it’s yet to be something I can physically do.

I can’t visit their grave myself. I can barely say the word grave in relation to my two babies. I’ve visited them on each of their birthdays, and that is it. I should go more often, I feel really bad that I don’t. But deep down I know that’s not where they are. They’re in my heart, and that is the only place they’ll always be.

well its been a long day, had major asthma attack last night, had to pull

out all the meds. when i talked to my Doctor today he said: keep your face

out of any and all vegetation. lol  (I'm sure he has someone come and do

his yard) So i went out and told those vines that they had not won the

war, they had just gotten a reprieve.

    My daughter in law Steffany went into premature labor yesterday, Doctors had a hard

time stopping it so pray for her and out little boy his lungs are not yet ready for this world.

    talked to her today they let her come home but she has to stay off her feet as much as possible, which is hard when u have 3 young children and a full time job. Well will it never end it's 12am so i guess it's no longer the 29th, always a day late. lol