Ipi - 3mg vs 10mg/kg - Increased OS with increased SE on 10!

Initially, folks with melanoma were treated with 10mg/kg of ipilimumab (now called Yervoy).  Side effects were clearly pretty bad for some on that regimen, so the powers that were...with the evidence that was...decided the difference in result was not worth suffering the side effects that resulted with 10mg/kg and going with the 3mg/kg dose for Stage IV peeps was the better part of valor.  For reasoning that makes sense only when dealing with the FDA....Stage III folks were still allowed (or forced...however you want to look at it) to take the 10mg/kg dose, because that was all that had been used in existing testing for them at that time.

Now...there's this:

Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial.  Ascierto, Del Vecchio, Robert, et al. Lancet Oncol. 2017 Mar 27.

A phase 2 trial suggested increased overall survival and increased incidence of treatment-related grade 3-4 adverse events with ipilimumab 10 mg/kg compared with ipilimumab 3 mg/kg in patients with advanced melanoma. We report a phase 3 trial comparing the benefit-risk profile of ipilimumab 10 mg/kg versus 3 mg/kg.

This randomised, double-blind, multicentre, phase 3 trial was done in 87 centres in 21 countries worldwide. Patients with untreated or previously treated unresectable stage III or IV melanoma, without previous treatment with BRAF inhibitors or immune checkpoint inhibitors, were randomly assigned (1:1) with an interactive voice response system by the permuted block method using block size 4 to ipilimumab 10 mg/kg or 3 mg/kg, administered by intravenous infusion for 90 min every 3 weeks for four doses. Patients were stratified by metastasis stage, previous treatment for metastatic melanoma, and Eastern Cooperative Oncology Group performance status. The patients, investigators, and site staff were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study treatment. This study is completed and was registered with ClinicalTrials.gov, number NCT01515189.

Between Feb 29, and July 9, 2012, 727 patients were enrolled and randomly assigned to ipilimumab 10 mg/kg (365 patients; 364 treated) or ipilimumab 3 mg/kg (362 patients; all treated). Median follow-up was 14·5 months for the ipilimumab 10 mg/kg group and 11·2 months for the ipilimumab 3 mg/kg group. Median overall survival was 15·7 months for ipilimumab 10 mg/kg compared with 11·5 months for ipilimumab 3 mg/kg. The most common grade 3-4 treatment-related adverse events were diarrhoea (37 [10%] of 364 patients in the 10 mg/kg group vs 21 [6%] of 362 patients in the 3 mg/kg group), colitis (19 [5%] vs nine [2%]), increased alanine aminotransferase (12 [3%] vs two [1%]), and hypophysitis (ten [3%] vs seven [2%]). Treatment-related serious adverse events were reported in 133 (37%) patients in the 10 mg/kg group and 66 (18%) patients in the 3 mg/kg group; four (1%) versus two (<1 adverse="" died="" events.="" from="" i="" patients="" treatment-related="">

In patients with advanced melanoma, ipilimumab 10 mg/kg resulted in significantly longer overall survival than did ipilimumab 3 mg/kg, but with increased treatment-related adverse events. Although the treatment landscape for advanced melanoma has changed since this study was initiated, the clinical use of ipilimumab in refractory patients with unmet medical needs could warrant further assessment.

So....from these results...it looks as though the overall survival difference was about 4 months or less  ~ 15·7 months for ipilimumab 10 mg/kg compared with 11·5 months for ipi 3mg/kg. To be honest, not sure what I would choose if I had to (or COULD) choose.

Wishing you my best....whatever you do, dear ratties!  (Will we EVER get to stop being ratties????!) - c

Pre-existing conditions, high risk pools and what changes in the ACA could do to you and yours!!!!

Man!  I promise you!  There is not ONE SINGLE family in this country who does not have at least one family member with a pre-existing condition....certainly as defined by insurance companies. Grandma and her high blood pressure?  Check!  Uncle Jo and his arthritis?  Check!  Little Nancy who spent a couple days in NICU right after birth?  Check!  Momma's asthma?  Absolutely!  Your melanoma?  Oh, yeah!!!  And to make it worse....if insurance companies/government entities were allowed to group folks in high risk pools as identified by THEM....that is one slippery slope indeed. Cause...that broken leg, that one time you needed a little counseling, those extra 20 pounds  (And NO!  I'm not kidding or being silly!!!) could easily be used to put YOU and YOURS in a high risk pool as an individual with a pre-existing condition!!!

For an explanation of what high risk pools mean and how they could affect us all....here's a little Op Ed from one of the smartest dudes I know:  

Let’s take a look at high risk pools for health insurance. An insurance pool is a way to group all the individuals covered by an insurance plan. They share the benefits and the costs of the insurance. The group can be defined in many ways: by a common employer, gender, place of residence, health status, health history like preexisting conditions, occupation, etc. In the case of high risk pools the grouping is done to choose those who are likely to have the most costly medical needs. Having placed the most costly patients in this high risk pool allows the insurance company to be more competitive in the market place for the remaining larger population. Thus, the high risk in these pools is for the insured. The low risk is for the insurance company. By shifting the cost of the most expensive consumers to those very consumers and government sources, high risk pools leave insurance companies with low risk pools for which they can charge lower premiums and make larger profits. Through placing the consumer in a high risk pool because of a preexisting condition, the insurance company shifts the financial exposure to the consumer. These premiums are much higher, often two or three times higher than those for the low risk pool. The coverage is worse often not covering essential services. The deductibles are very large. There are annual and lifetime caps. There is often a gap of 6-12 months before coverage starts. The networks of providers and services are limited. Drug formularies are restricted. To date, experience with high risk pools has demonstrated their woeful inadequacy. Even when correcting for some of the factors restricting access as in the PCIP(Preexisting Condition Insurance Plan), the high risk pool run by the federal government in order to transition to the ACA, only 1-2% of the estimated 27% of the population with preexisting conditions was covered. The PCIP, as well as the state plans in place before the ACA, all suffered from the same problems: Sequestering sicker consumers removed the market based incentive for discounts based on volume. Lack of comprehensive coverage decreased health maintenance. High premiums and deductibles made the subscriber pool unstable. All in all this resulted in poor coverage at great expense for the government and the individuals.

The basic flaw in utilizing high risk pools is that this approach fails to recognize the buffering effect created when as large a portion of a population as possible is included in the risk pool. The basis of insurance is that while the level of risk for most individuals is low, those who are at high risk changes constantly and rapidly. By sharing risk generally, with low and high risk individuals combined, while recognizing that at any moment one may move from the low to the high risk group and vice versa, the risk for the group as a whole is stabilized. Though the whole population may have a slight rise in premiums no one individual is devastated. Shared risk better protects the group all together. Health insurance is something we all use eventually. The buffering effect is also evident with the inclusion of all ages, all genders, and all diseases into the risk pool. The converse is for each individual to bear their own risk. Using high risk pools is an example of this converse approach. For the reasons stated above this is both financially and socially ineffective. It does not produce the most good for the most people. So, in this instance, insistence on the most inclusive pool is the most financially sound within a socially beneficial context. Looking at the examples in the world where this has been put into practice reveals better care at lower cost for whole populations.

The founding principle for health insurance should be the Three Musketeers’ motto ,"One for All and All for One". The principle behind the Republican Plans is the morally myopic Ann Rand motto, "All for Me and Me for Me". A principle that hasn’t worked for the common good and never will.                                             ~ Brent S Morris, MD

Folks, we can be completely, totally well....eating healthy food, running, working and paying taxes one minute, but despite all that, be hit by a Mac truck (or melanoma) the next!!!  Still, if like me, you have good care, a little luck, and some determination, you can rejoin the healthy.  I have always paid my taxes...when sick or well.  I have never be "given " insurance...I bought my own...albeit through the ACA...since before its implementation, I had a pre-existing condition!!!  Folks may have times when they need our help!  However, if we give that assistance, through our generosity of spirit and inclusive insurance pools - many, many illness and injuries can be successfully treated allowing folks affected to not only live the life we all deserve, but return to the working, tax paying world, to financially uplift us all.  

Thank about it!  (And FYI!!!  Despite what my insurance company has had to pay due to my melanoma....they STILL made money on me!!  Yep!  I did the math!!!)  - c

The mice told us so....Cardiac toxicity and immunotherapy

The mice told us this a long, long, long time ago.  In fact, "What about the cardiomyopathy in those mice???" was one of the first questions Brent asked of Dr. Weber when I started my nivo/Opdivo trial in 2010.

Since then we have learned about a great number of side effects from immunotherapy....including a variety of cardiac related problems.  Here is the last installment (with links within):  Side effects of immunotherapy - Part 7

Now there's this:

Immune Checkpoint Inhibitors and Cardiac Toxicity: An Emerging Issue. Varricchi, Maron, Mercurio, et al. Curr Med Chem. 2017 Apr 7.

Although survival of patients with different types of cancer has improved, cardiotoxicity induced by anti-neoplastic drugs remains a critical issue. Cardiac dysfunction after treatment with anthracyclines has historically been a major problem. However, also targeted therapies and biological molecules can induce reversible and irreversible cardiac dysfunction. Cancer immunotherapies over the last years have revolutionized the clinical management of a wide spectrum of solid and hematopoietic malignancies previously endowed with poor prognosis. At the forefront of immunotherapy are immune checkpoint inhibitors: the two most prominent are the targeting of cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) and of programmed cell death 1 (PD-1) and its ligand PD-L1. Ipilimumab (anti-CTLA-4) is the godfather of checkpoint inhibitors, whereas several blocking monoclonal antibodies targeting PD-1 (nivolumab and pembrolizumab) and PD-L1 (atezolizumab, durvalumab, avelumab, and BMS-946559) have been developed. Inhibitors of CTLA-4 and PD-1/PD-L1 pathway can unleash anti-tumor immunity and mediate cancer regressions. Although CTLA-4 inhibitors and PD-1 and PD-L1 blocking agents are frequently associated with a wide spectrum of immune-related adverse events, cardiac toxicity has been underestimated. However, early animal studies have demonstrated that after CTLA-4 inhibition and PD-1 deletion autoimmune myocarditis can occur. Moreover, PD-1 and PD-L1 can be expressed in rodent and human cardiomyocytes. During the last years several cases of fatal heart failure have been documented in melanoma patients treated with checkpoint inhibitors. The recent experience with cardiovascular toxic effects associated with checkpoint inhibitors introduces important concepts biologically and clinically relevant for future oncology trials and clinical practice.

The obvious difficulty of course remains....if you have Stage IV melanoma...you need treatment or you will die.  Side effects seem small when faced with that dilemma.  However, knowledge can equal power. While I did have to have an EKG prior to starting my treatment, no further cardiac studies have been done.  I have had no symptoms that would indicate their need...but perhaps better screening prior to, a clear follow-up plan and close observation with RECOGNITION of potential problems, could save more folks SOONER!!! Hang tough ratties!!! - c

Radiologic f/u for melanoma patients with stable diease - CT or PET????

The best radiologic evaluation of melanoma patients' disease status/progression and how to interpret those results has been one of the many adjustments needed among researchers, oncologists and radiologists since use of immunotherapy began.  Pseudoprogression, tumors that stop growing but don't go completely away, development of pneumonitis and lung nodules - are just a few of the many problems that have had to be considered.  Here is an earlier post that discussed how researchers were looking at these issues:  Radiological evaluation of response to melanoma treatments

Now there is this ~

Stable disease or complete response? A critical evaluation of the radiologic response to immune checkpoint blockade in advanced melanoma. Tietze, Heppt, Angelova, et al.
Hautarzt. 2017 Apr 5. 

Rating the response of melanoma to immune checkpoint blockade (ICB) by conventional CT proves to be difficult, since response patterns and kinetics differ from the classical responses seen with other therapies. Hence, immune-related response criteria were developed. However, they are mainly based on the alteration of the diameter of lesions over time but do not include metabolic activity.

The aim of this study was to search for additional criteria to improve the interpretation of the radiologic images of patients with metastatic melanoma after ICB.

We retrospectively analysed 7 patients with metastatic melanoma over a period of 13-41 months after treatment with ICB using contrast enhanced CT scans from the neck region to the lower abdomen and compared the results in the follow ups with ¹⁸F-FDG PET/CT.

Metastatic lesions in 5 of 7 patients rated as stable disease (SD) in CT staging showed no metabolic activity in ¹⁸F-FDG PET/CT. The size of these lesions did not increase or show metabolic activity in the further follow-up, even after discontinuation of ICB. In contrast, tumor lesions in the other 2 patients rated as SD in CT staging showed metabolic activity in ¹⁸F-FDG PET/CT. These tumor lesions expanded significantly in the further course of the disease.

In addition to the size of a tumor lesion, its metabolic activity adds important information regarding treatment response. Thus, we propose that the metabolic activity assessed with ¹⁸F-FDG-PET/CT should be included in the immune response criteria. No FDG uptake in a lesion should be rated as inactive tumor rather than SD and further treatment may not be required.

Given this report, if I were a patient with stable disease on CT....I would want a PET to look for FDG uptake.  No uptake????  THEN I would consider myself with stable disease and feel much better about going off therapy!!!  For what it's worth! - c

The Mental Price of Melanoma

Given the many pleas and posts and requests for help that I've seen or have been sent directly regarding stress and worries and fears when peeps are given the diagnosis of melanoma....I thought the first article might demonstrate that you are not alone, though most folks diagnosed with melanoma have a "very good prognosis" (See?  I'm not the ONLY person saying that!!!) and the approach spelled out in the second might provide some useful information - 

Fear of new or recurrent melanoma after treatment for localised melanoma. Bell, Mehta, Turner, et al. Psychooncology. 2017 Jan 4.  

To estimate the amount of fear of new or recurrent melanoma among people treated for localized melanoma in an Australian specialist centre.  We randomly selected 400 potential participants from all those treated for localised melanoma at the Melanoma Institute Australia during 2014 (n = 902). They were asked to complete an adapted version of the Fear of Cancer Recurrence Inventory (FCRI). We calculated summary statistics for demographics, clinical variables and total FCRI and subscale scores.  215 people (54%) completed the FCRI questionnaire. The overall mean severity subscale score was was 15. A high proportion of participants had scores above a proposed threshold to screen for clinical fear of cancer recurrence (77% and 63% of participants with and without new or recurrent melanoma had severity subscale scores greater or = to 13). Most participants also had scores above a threshold found to have high specificity for clinical fear of cancer recurrence (65% and 48% of participants with and without new or recurrent melanoma had severity subscale scores greater or = to 6). The severity subscale appeared to discriminate well between groups with differing levels of risk of new or recurrent melanoma.  There is a substantial amount of fear of new or recurrent melanoma among this population, despite most having a very good prognosis.


Psychoeducational Intervention to Reduce Fear of Cancer Recurrence in People at High Risk of Developing Another Primary Melanoma: Results of a Randomized Controlled Trial. Dieng, Butow, Costa, et al. J Clin Oncol. 2016 Dec 20.   

People with a history of melanoma commonly report a fear of cancer recurrence (FCR), yet psychologic support is not routinely offered as part of ongoing melanoma care. This randomized controlled trial examined the efficacy of a psychoeducational intervention to reduce FCR and improve psychologic adjustment in this patient group compared with usual care. 
 
The intervention comprised a newly developed psychoeducational resource and three telephone-based psychotherapeutic sessions over a 1-month period timed in accordance with dermatologic appointments. Participants were randomly assigned to intervention (n = 80) or usual care (n = 84). Assessments were completed at baseline, 1 month, and 6 months after dermatologic appointments. Linear mixed models were used to examine differences between treatment and control groups for patient-reported outcomes, including FCR, anxiety, stress, depression, melanoma-related knowledge, health behaviors, satisfaction with melanoma care, unmet needs, and health-related quality of life. 
 
At 6 months, the intervention group reported lower FCR severity, trigger, and distress scores than the control group in the baseline-adjusted models; the between-group mean difference was -1.9 for FCR severity, -2.0 for FCR triggers, and -0.7 for FCR distress. The decrease in FCR severity (but not triggers or distress) remained statistically significant after adjustment for other covariates. At 6 months, the intervention group also reported lower stress and improved melanoma-related knowledge compared with the control group. No differences were found between groups for other secondary outcomes.
 
This newly developed evidence-based psychoeducational intervention was effective in reducing FCR and stress and increasing melanoma-related knowledge in people at high risk for another melanoma.

If you as the patient or as a family member are having trouble dealing with the psychological burden of melanoma and its treatments...seek help.  Your doc may not offer it, but you can certainly ask for it!!!  And sometimes....it really helps to just - phone a friend!!! - c

Perception....patient vs doctors in cancer care

I touched on this report when it came out of the Boston meeting here:  Patients vs Docs - Treatment goals for cancer patients

Patient Versus Physician Valuation of Durable Survival Gains: Implications for Value Framework Assessments. Shafrin, Schwartz, Okoro, Romley. Value Health. 2017 Feb;20.

Previous research indicates that patients value therapies that provide durable or tail-of-the-curve survival gains, but it is unclear whether physicians share these preferences.
To compare patient and physician preferences for treatments with a positive probability of durable survival gains relative to those with fixed survival gains.

Patients with advanced stage melanoma or lung cancer and the oncologists who treated these patients were surveyed. The primary end point was the share of respondents who selected a therapy with a variable survival profile, with some patients experiencing long-term durable survival and others experiencing much shorter survival, compared to a therapy with a fixed survival duration. Parameter estimation by sequential testing was applied to calculate the length of nonvarying survival that would make respondents indifferent between that survival and therapy with durable survival.

The sample comprised 165 patients (lung = 84, melanoma = 81) and 98 physicians. For lung cancer, 65.5% of patients preferred the therapy with a variable survival profile, compared with 40.8% of physicians. For melanoma, these figures were 63.0% for patients and 29.7% for physicians . Patients' indifference point implied that therapies with a variable survival profile are preferred unless the treatment with fixed survival had 13.6 months (melanoma) or 11.6 months (lung) longer mean survival; physicians would prescribe treatments with a fixed survival if the treatment had 7.5 months (melanoma) or 1.0 month (lung) shorter survival than the variable survival profile. 

Patients place a high value on therapies that provide a chance of durable or "tail-of-the-curve" survival, whereas physicians do not. Value frameworks should incorporate measures of tail-of-the-curve survival gains into their methodologies.

Just putting it out there one more one!!  A patient's perspective should be INCLUDED (at the very least) in their own health care decisions AND in research/trial development and implementation!!!  Cause, yeah!  We ratties...as noted in the middle of this post:  Nivolumab Shows Impressive OS in melanoma...be riding the tail!!!

Hang tough and fight for the treatment YOU think best for YOU!!! - c

Sew Chaotically! - Fit and flare top - B5890

I've had this pattern for a while and finally stitched one up for Roo as part of her spring wardrobe update!!!  Spring Tops!!!

Here, I used a light weight seersucker from either JoAnn's or Hancock (back in the day!!) and the collarless version of D (ever so slightly shorter due to limited yardage).

It sewed up beautifully!!!  The tucks (pleats?) are interestingly made and super easy!  My only change was to make the neckline a little lower in the front.  (Left per the pattern indications it would have been high, y'all!)

Rosie's went together so easily and was so cute I made myself one!!!

This one is a sleeveless view A, again with the lowered neckline.  I am proud of the pattern placement!  A challenge only because of limited yardage, but still.  I love how this one looks, but because it is made of quilting cotton (purchased before I knew the difference) it does require ironing, which is a bit of a pain.

On the flip side, making my own binding from the fabric was easy peasy since it took to the iron very well!  Previously, this was something I thought I'd never do.  But I rather liked making it and using it has been a treat!!

The third is the charm!!  This one is full length view D (without collar and with the slight neckline modification) in a seersucker that was a little heavier than the one for Roo.  Gotta say, seersucker works very well for this pattern as it holds the drape without being stiff and no ironing is required!

I added a little button with loop to the top of this one.

And while it needs to get a little warmer to enjoy wearing it at home, it was super fun to wear during our little "spring break"!  Travel Chaotically! - The Gulf Coast - Spring Break and Me Mades, Baby!!!

This is a fun little top that fits very well!!  Maybe I should make it into a dress!!!!  Sew Chaotically! - les