3 ms·

I agree that my original comment is very optimistic--for what it's worth, Keytruda has thus far been very effective in the case I'm talking about, so I have som

by nyx 4y ago

I agree that my original comment is very optimistic--for what it's worth, Keytruda has thus far been very effective in the case I'm talking about, so I have some bias here. I concede that even in my "double the effectiveness" example, we're talking about doubling something like a 20% 5-year OS. By "around the corner" I'm really talking about, like, 20-30 years out, which I think is fairly soon in terms of cancer treatment progress. You're right that it reads like a leap in the context of my comment.

bnjemian 4y ago
Not to be too pessimistic, but 600,000 people died of cancer in 2019, so 20-30 years is hardly "round the corner" when you extrapolate to the, let's say conservatively, 10 million families in the US losing loved ones in that time period. The history of cancer (The Emperor of All Maladies is a good book covering the history) is full of promising adjuvants, drugs, protocols that fail to generalize well. There are a lot of reasons for this. With drugs, one is that Phase 3 clinical trials often have patients who are selected on the basis of them being likely to be among the best responders. But once the drug is approved and made available to all patients within a given indication – a fundamentally different population – an overwhelming positive response may be significantly more modest. In many cases, this has to do with a patient's tolerance of the side effects or the interaction of the drug with known or underlying comorbidities. While I'm encouraged by the research in this article and could see the drug being part of a combination protocol, I'm hesitant that it will be "universal". And the mechanism, candidly, is downright scary – if I were running a Phase 3 for this (seems the trial cited was a Phase 2 demonstrating baseline safety in humans), I would want a very detailed articulation of how the technology ensures with a high margin of safety that the drug delivery is targeted to the tumor and no other tissues. The permeability of blood vessels in tumors would not be sufficient (and also does not seem "universal"). On a more personal note, I'm actually a computational biologist and have done quite a bit of work in cancer research (masters thesis, portion of my dissertation). My Mother was also diagnosed with a highly aggressive cancer of unknown primary (CUP) origin in her lung late last year (estimated stage IIIb for NSCLC, stage 4 for CUP/melanoma). Its location and heart involvement made it inoperable. Turned out is was a melanoma, which to be frank I quickly recognized down to the subtype upon reviewing the pathology reports. The lung oncologists were much more conservative; given the location, they weren't especially well-versed in melanoma, and presumed it was an adenocarcinoma with a rare presentation despite the staining for carcinomas being negative across the board. Luckily, we managed to convince them to split the difference on the standard of care – CarboTaxol (carboplatin + taxol) combination and immunotherapy (nivolumab and ipilimumab), all at once. The immunotherapy surely saved her life; unlike with carcinomas, chemo is roughly 5% effective (as in, any response whatsoever) for melanomas. About 70% of melanoma diagnoses respond to combination immunotherapy with about 15% going into full remission (memory is shaky on that last number, may be slightly higher). With >95 PDL-1 expression, she was one of the lucky ones – she had a full response on both imaging and pathological endpoints. That also made her tumor (or what was left of it) operable. She's two lobes and a chunk of heart lighter, but she's alive, healthy, and recovering well. And while I cringed when he did it, one of her oncologists dropped the "c word" after surgery in discussing her case. Knowing the foe, I'm much more cautious in contemplating whether any of this represents a cure. Psychologically, the uncertainty around the future maintains a heavy burden over her and our family. A 70% response rate sounds really good, but it's a very different calculus when you're living it. But as you said, her path towards a cure wouldn't have been possible not too long ago – in her case, 10-15 years; ipilimumab was approved in 2011 and nivolumab in 2014. But 30% of people with melanoma are still non-responders to combination immunotherapy. And, while a handful of other (generally less effective) options exist, non-responses in melanoma are deadly, often within a year or two of diagnosis, and for most all cancers have an incredibly high opportunity cost.
- notdonspaulding 4y ago
  My Dad is currently battling a GBM. Do you have any advice for a web dev who wants to get his toe in the door of understanding the computational biology of gliomas? I don't expect I'll be able to do much, but all of the treatments we've undertaken so far seem very dated (not able to resect, one round of radiation, temodar+avastin for the last year, just switched to CCNU+avastin). I'd love to know where the state of the art is at and know how to nudge/prompt his oncologists to be looking at it through that lens. My email is in my profile, feel free to reach out privately.
  - clokar 4y ago
    Have you tried blood/tissue based comprehensive genomic profiling testing ? This might help understand the genomic determinants of the tumor, possibly helping the treating physician make an informed decision on treatment choice.

by nyx 4y ago

bnjemian 4y ago

Not to be too pessimistic, but 600,000 people died of cancer in 2019, so 20-30 years is hardly "round the corner" when you extrapolate to the, let's say conservatively, 10 million families in the US losing loved ones in that time period. The history of cancer (The Emperor of All Maladies is a good book covering the history) is full of promising adjuvants, drugs, protocols that fail to generalize well. There are a lot of reasons for this. With drugs, one is that Phase 3 clinical trials often have patients who are selected on the basis of them being likely to be among the best responders. But once the drug is approved and made available to all patients within a given indication – a fundamentally different population – an overwhelming positive response may be significantly more modest. In many cases, this has to do with a patient's tolerance of the side effects or the interaction of the drug with known or underlying comorbidities. While I'm encouraged by the research in this article and could see the drug being part of a combination protocol, I'm hesitant that it will be "universal". And the mechanism, candidly, is downright scary – if I were running a Phase 3 for this (seems the trial cited was a Phase 2 demonstrating baseline safety in humans), I would want a very detailed articulation of how the technology ensures with a high margin of safety that the drug delivery is targeted to the tumor and no other tissues. The permeability of blood vessels in tumors would not be sufficient (and also does not seem "universal"). On a more personal note, I'm actually a computational biologist and have done quite a bit of work in cancer research (masters thesis, portion of my dissertation). My Mother was also diagnosed with a highly aggressive cancer of unknown primary (CUP) origin in her lung late last year (estimated stage IIIb for NSCLC, stage 4 for CUP/melanoma). Its location and heart involvement made it inoperable. Turned out is was a melanoma, which to be frank I quickly recognized down to the subtype upon reviewing the pathology reports. The lung oncologists were much more conservative; given the location, they weren't especially well-versed in melanoma, and presumed it was an adenocarcinoma with a rare presentation despite the staining for carcinomas being negative across the board. Luckily, we managed to convince them to split the difference on the standard of care – CarboTaxol (carboplatin + taxol) combination and immunotherapy (nivolumab and ipilimumab), all at once. The immunotherapy surely saved her life; unlike with carcinomas, chemo is roughly 5% effective (as in, any response whatsoever) for melanomas. About 70% of melanoma diagnoses respond to combination immunotherapy with about 15% going into full remission (memory is shaky on that last number, may be slightly higher). With >95 PDL-1 expression, she was one of the lucky ones – she had a full response on both imaging and pathological endpoints. That also made her tumor (or what was left of it) operable. She's two lobes and a chunk of heart lighter, but she's alive, healthy, and recovering well. And while I cringed when he did it, one of her oncologists dropped the "c word" after surgery in discussing her case. Knowing the foe, I'm much more cautious in contemplating whether any of this represents a cure. Psychologically, the uncertainty around the future maintains a heavy burden over her and our family. A 70% response rate sounds really good, but it's a very different calculus when you're living it. But as you said, her path towards a cure wouldn't have been possible not too long ago – in her case, 10-15 years; ipilimumab was approved in 2011 and nivolumab in 2014. But 30% of people with melanoma are still non-responders to combination immunotherapy. And, while a handful of other (generally less effective) options exist, non-responses in melanoma are deadly, often within a year or two of diagnosis, and for most all cancers have an incredibly high opportunity cost.

notdonspaulding 4y ago
My Dad is currently battling a GBM. Do you have any advice for a web dev who wants to get his toe in the door of understanding the computational biology of gliomas? I don't expect I'll be able to do much, but all of the treatments we've undertaken so far seem very dated (not able to resect, one round of radiation, temodar+avastin for the last year, just switched to CCNU+avastin). I'd love to know where the state of the art is at and know how to nudge/prompt his oncologists to be looking at it through that lens. My email is in my profile, feel free to reach out privately.
- clokar 4y ago
  Have you tried blood/tissue based comprehensive genomic profiling testing ? This might help understand the genomic determinants of the tumor, possibly helping the treating physician make an informed decision on treatment choice.