ONCY announces positive Ph III Head and neck results on the patients with locoregional disease. Trial patients with metastatic disease have not reached survival unblinding trigger at this time.

http://tiny.cc/nxjw6w

cheers, Geneman

I was at this talk. Interesting that there was no improvement in PFS at all yet they showed an improvement in OS. One of the moderators pointed out that the entire survival benefit may be attributed to GMCSF ameliorating some of Ipi's "horrendous side effect profile" (her words, not mine).

Bottom line is that GMCSF, by itself, is not even close to an appropriate comparator in 2013. They will need to re-think their approach.

cheers, Geneman

TVEC achieved all of it's primary endpoints with p values that were all in the 0.0001 range. The relative risk for progression was 0.13. The time to treatment failure was similarly spectacular. The data for overall survival endpoint has not come close to maturing as a large percentage of the treated group are still alive but censored (as dead) for this second analysis. A quick look at the survival KM shows a very large cohort of survivors in the middle of the treated survival curve. It won't take very much time for these survivors to influence the HR and the p values as the trial matures. The slopes of the curves differ by more than 20% but the censoring of the survivors really influences the data in the middle of the curve.
Doesn't really matter. Amgen tested TVEC against subcutaneous GMCSF, not against any of the current active agents. The comparator isn't valid to any evaluation for approval. Despite Amgen touting the data as evidence of Oncolytic Immunotherapy, there are no immunological data at all. The response data are a bit difficult to decipher as the company looked at a variable number of lesions to determine progression and injected a variable number of lesions, cutaneous and deep. Lots of other quibbling with the data.

Regardless, this provides an example of a successful Ph III trial of an oncolytic virus in a very difficult indication where early responses translate into an overall survival benefit. Amgen will now have to figure out what to do with this "proof of principle" Ph III study. They will either need to pair TVEC with new agents in melanoma and complete another Ph III or move into another indication.....or drop TVEC. Time will tell.

cheers, Geneman

PPHM data Very interesting conversations about this Ph II randomized data. The data are the data and the clinical significance will not be determined by this particular set of numbers. I find it fascinating how the argument turns 180 degrees when the randomized data don't fit with conventional wisdom. All of a sudden, the pariah of statistical analysis - survival from a historical perspective - emerges as a critique of the "gold standard" randomized data. It seems the sacred status of the randomized trial is conditional upon the impression of the results. If the data support the pre-ordained outcome....the randomized trial has triumphed. If the numbers don't jive, historical stats are trotted out to malign the randomized data. Historical data are either reliable or not (In general, not) but this appears to be a discussion of opinion/convenience rather than statistics. If the data had pointed in the other direction, the pundits would have been strident in their comments about depending upon historical data to design a failed trial.

I am neither a fan of "historical data" or blind advocacy of randomized data and this is not a comment on the PPHM trial. Their numbers will have to suffer the swords and artillery of the peer community. They will examine the process and the enrolment characteristics. A fine tooth comb over the progression and survival data. After all of the slicing and dicing, a much more lean understanding will emerge from these data. That understanding will be developed by dissecting the actual trial but not by tossing up external comparators (relevant or irrelevant).

I just find it interesting how "historical data" finds new respect in this situation. Maybe the influence of randomized data is a little more subjective than we would think.

Cheers, Geneman

The Mitas have had a busy 2 years as they have transitioned to Cedars. I believe that I have seen the combined data from the two studies in some presentation but I can't put my finger on the slides or figures. I know that there has been numerous references to the platinum and taxane exposure profiles for the patients.

Agreed that the histological profile of HNSCC is heterogeneous but, across the board, they are EGFR and Ras activated as a common feature.....much like the squamous cell lung story. The exact histology may not be the critical feature predicting success but rather the MOA involving Ras activation. Bit of a thought shift, exploiting the cancer drivers rather than treatment by cell type.

We will know pretty soon. The process will be validated or disproved in the "not too distant future".

I hate that term!!

Cheers, Geneman

ONCY PFS and OS You ask a whole bunch of questions that do not have a single answer.

First, the statistical design has been developed with Donald Berry as the Company's consultant. He has been the champion of Adaptive Stats in cancer for many years. You can look up his contact email and discuss this in depth. He is at MD Anderson.

Kristine Broglio and Berry wrote a JNCI paper in 2009 discussing the reliability of PFS numbers in predicting OS. Bottom line, for conditions where overall survival was a 1 year and the survival post progression was 2 months, the correlation was extremely tight. In such situations (as in HNSCC), a statistically significant PFS was at least 90% predictive of a significant OS.

As you examine conditions that have longer median survivals and longer survival post treatment, the correlation between PFS and OS falls off to 20% when there was longer survival and more than 24m post treatment survival. The more nasty the disease and the quicker the progression; the better the correlation is between PFS and OS. This concept has been debated lots at the level of the FDA, Health Canada and EMEA in the last few years. It remains a hot topic....it is cheaper and dirtier to depend on a surrogate like PFS but the agencies have been burnt too many times recently in breast, prostate, renal cancers.

The blind must be broken to determine the additions stats. If the two PFS curves suggest a liklihood of survival success of greater than 70% (in a trial of 400 patients), the Part II of the trial is a go. It is way more complicated than that but it gets over my head and I get too dizzy trying to keep all of the pieces separate.

The US H+N results were presented last November by Monica Mita and Anand Kardad at the AACR/EORTC Molecular Targets meeting in San Francisco.

gotta go

Cheers, Geneman

As RJC has said, small cancer biotechs that end up being successful develop a treatments with a known mechanism of action; having a large market potential; easy and reliably manufactured; have reliable systems of administration; have broad IP coverage; demonstrably safe and are clinically effective.

Larger biotechs have no reason to scoop up these fledgling companies until most of these boxes are ticked. For the big companies, $2-10B represents an rounding error in their financing. They want the company to be de-risked before making a play. Most of the time, they dip their toes in with a partnership and some loose change ($200M) and watch how the milestones play out. If things go well, the milestones are paid out, the Biotech increases the holding until they control the company.

The reason that the H+N (and Pancreatic) data are so pivotal is the nature of randomized data. This type of data is strongly predictive of eventual Ph III success and registration with the FDA. Non-randomized trials are just noise to the big companies. ONCY would alter it's outlook from 30% success to >90%, if H+N and pancreatic both show survival benefit in the two small randomized trials that are due to report. These data brings out the suitors and success would allow ONCY to cross over the hurdle to be recognized as a true Ph III entity........a status prized by large Pharma and Biotech.

Currently, we are flaunting H+N results from two trials (totalling just over 30 patients) that shows unexpected results. If I were shopping around for a company, I would say "nice.....where are the randomized data?.........call me then and we'll talk". A large Biotech could buy the company for $500M right now with current data or wait until the randomized data and make a decision. If the numbers look good, they progressively buy the company over a couple of years. If the results are ambiguous, they bail (with everyone else). With successful randomized trials, the big companies don't care if it eventually costs them $5B.......for a company that could sell that much product per year. They only care about de-risking.

Lots of investigators and scientists are convinced that Reovirus can work as an anti-cancer agent. It is "new" and interesting and is worth exploratory trials. The fact that NCIC and NCI are backing the studies is great but their endorsement should not influence you too much. There are lots of other factors at play when they take on novel approaches to cancer therapy.

If the H+N trial collapses, the effect on the company will be chilling. The market will not look at such a result rationally and will not look at the "pipeline" with any respect. The company was charged with taking it's best prospect forward to the FDA......if it fails on this very minimal initial hurdle, investors will be very sceptical of the entire program and the company will be punished. It will take years to re-establish confidence and the company will not be able to raise capital.

This is why these data are pivotal and that is why the company is at risk of a complete flameout if these data conclude that the H+N program is futile. Binary indeed!!

Cheers, Geneman

This is not to anyone in particular but rather a comment on the various superficial ONCY analyses that are cropping up.

Tough to respond to the various criticisms of the Oncy story from elsewhere on the net. Suffice to say that one has to dig into this story deeply before it can be even partially understood. It is not enough to blithely state that the company is too small, the approach has been too fragmented, the strategy is too novel, the results are obscure, they don't have randomized data, they have been around too long...... Most new biotechs don't make it. Most Ph 1 trials are failures. Most Ph III trials were conjured up after anecdotal evidence of effect followed up with relatively small Ph II trials. All novel therapies endure decades of scorn; followed by a decade of disbelief; followed by 10 years of "overnight success" where "everyone knew" it was the treatment of the future. ONCY is in the midst of such a process. If the company can prove that Reolysin produces a clinical anti-cancer effect, it will herald a new option for cancer patients and will be the talk of the town. If the trials fail, the company will flame out.

The most difficult feature to understand about the ONCY trials is the grave nature of the treated population. Many people do not appreciate how sick the treated patients are. When H+N cancer patients are first diagnosed, they are considered chemo/radiation naive and most respond to radiation and surgery. Advanced cases or patients that fail radiation then move on to multiple forms of chemotherapy, usually failing 2 more regimens. They become entirely resistant to radiation and conventional chemotherapy. After this happens, their life expectancy is measured at about 20 weeks. This is the heavily treated, multiply resistant, advanced H+N cancer patient profile that enrol in the ONCY studies. The patient population that is being treated in the ONCY Ph III trial is the worst of the worst and they are already deep into their Kaplan Meier survival curve when they are offered Reolysin. The expectations for disease progression and survival are dramatically different than treatment naive (or minimally treated) patients. Over and over, in many studies, the patients with multiply resistant and rapidly advancing disease have been shown to respond poorly (< 10% RECIST response rates) and have median progression ~6-8 weeks (1-2 CT scans) and median survival of less than 22 weeks. Numerous critics of the ONCY approach fail to appreciate the differences between trial protocols and the treatment differences and expectations at different phases of the progression of the disease. ONCY is working in the last 20 weeks of the Kaplan Meier curve; most of the other treatments are starting with 50-200 weeks remaining on the KM curves. ONCY is working with the last 20 weeks of life......they have to show a statistically significant improvement of survival starting therapy with multiply resistant, terribly advanced patients. Not for the faint of heart!!!

I don't mind having discussions with the others about this but the talk has to focus on apples vs apples. The more you dig into the story, the more intriguing it becomes. ONCY is not still around 12 years later because it is a scam, but rather, the company is chasing down a novel mechanism of treating cancer. Lots of unknowns and lots of surprises along the way. This is not INGN, GNTA or many of the other failed treatment modalities (or even other failed viral modalities). The company is about to address the most valid concern about Reolysin as an anti-cancer agent; the lack of randomized survival data. These data are game changers. If unambiguously positive, all of the nay-sayers will have to sit up and notice. If the data bewilder us, head for the hills!!!

The battle against lethal cancers is incrementally fought. ONCY is up against some formidable cancers with virtually no real advances in treatment for decades. It is a very high risk game with potentially, some very high rewards. We are at the door knocking......Is anyone home??

Cheers, Geneman

My oxymoron alert went off when you wrote "completely transparent" in a paragraph about any biotech and their protocols/results. You have been involved or at least watched the obfuscation and tap-dancing of dozens of CEOs and CSOs when asked direct questions about trial issues. I have never expected transparency from any biotech and we all spend lots of time trying to unwind the confusion (ie: this board).

I don't think that the Ph III protocol is very complicated at all. Part 1 has to pass a PFS endpoint for the trial to continue. The primary endpoint for the entire trial is survival. The survival of the patients in Part 1 can be followed in parallel to the enrolling of part 2 and the total enrolment is adapted to the stats of Part 1. As compared to HIV, Alzheimer, MS, Prostate cancer, obesity trials, these stats are a walk in the park. Not much screwing around with a primary endpoint of overall survival.

All of my information comes directly from conference call questions, conference discussions or calls to the company. I attend the conferences where the raw data is presented. After lots of talking, the information slowly crystalizes.....it is not perfect, but it is better than a guess or conjecture. Sometimes, conflicting ideas come up and it is time for a call to the company. I find them pretty open to discussion if you ask reasonable questions.

Cheers, Geneman

ONCY Those press releases are very carefully crafted. Once the trial population reaches 12 weeks, the company will complete the analysis.....this does not say that they will complete the analysis at 12 weeks (or even on the 12 week data), it just says that they will do an analysis after that maturity date.

It is my understanding that Part 1 and Part 2 of the Ph III trial will be treated as separate trials within one. Obviously, the unblinding of the first 80 patients would compromise the rest of the statistical analysis through another 400 patients. I think the unblinding of Part 1 will lead to a survival analysis at 6m and 1y. Part 2 has started fresh at Patient 1 and will be completely blinded until enrolment is complete. There would be interval evaluations of progression free survival at landmark patient enrolment numbers (no or minimal statistical penalty). Additionally, more mature survival data would be evolving in parallel from Part 1 and could be publicly available. The Adaptive statistical package allows for the evolving clinical results of Part 1 to be used to understand/predict the performance of Part II.

How much data the company gives to us is a different story, I am afraid!! Often the provided information is limited and critical raw data is considered to be "secret". I am pretty sure that the defined survival numbers from Part 1 are partly to be used to define enrolment numbers for Part 2. This is the way I understand it, anyways.

Clarifying this would be a good topic for the question period after one of the company's conference calls.....there will be one coming up, no matter what.

Cheers, Geneman

ONCY At the end of 6 weeks, the CRO would have done a "data scrub" on all 80 patients. This would have covered off all of the demographics, the background clinical information and loose bits on the ITT patient group. The evaluation at 12 weeks should involve the collection of the interim clinical data, two blinded evaluations of the RECIST evaluations and delivery to the statistician(s). The statistician looks at the single (unblinded - all 80 patients) curve and compares these data to the data expected from a very well performing (upper percentile survival/progression) historical "control" group. From this statistical analysis comes the stats about clinical effect of Reolysin. The curve for all 80 patients would contain 40 "control" patients and 40 patients treated with Reolysin and, blinded, this 80 patient curve should look moderately better than a control curve. It is the job of the statistician to opine about the likelihood that unblinding the trial (80 patients) would produce a observable difference between treatment (40 patients) and control group (40 patients).

The language of the statistical analysis provided to the company is intentionally non-committal. For example, the company may hear many options......"there is an 80% chance that the data will resolve to (at least) a 6 week improvement in PFS"; "there is a 90% chance that the data will resolve to (at least) a 4 week improvement in PFS": "there is a 95% chance that the data will resolve to (at least) a 2 week improvement in PFS. In fact, the statistician would produce a pretty, curved dataset plotting an observable PFS difference vs. likelihood. There would be many iterations of the data provided to the company.......all before unblinding. The company looks at the data and decides about unblinding......or not. The CRO collects and scrubs the data; the stats person tortures the numbers and provides a "best guess" about the trends of the unblinded data; the company decides on the unblinding and subsequent statistical analysis.

The devil is in the SPA details. At what point is the company forced to unblind the trial? At what point will the company unblind the trial? We have heard 6 weeks, 12 weeks and, yet we are now past 18 weeks. To play the devil's advocate, if the stats person came to you after the 12 week scans and said that there is an 80% chance that the data are currently stat sig for a 6 week PFS difference (doubling of PFS), would you risk unblinding the trial? In a trial trending toward success, you are taking a 20% chance of negative stats (often spuriously negative) and a resultant futility decision that torpedoes the entire Ph III H+N program. What numbers convince you to unblind? How much risk to the entire Ph III program do you assume to see the data early?

As the data mature, so do the stats. At the 18 week scan, the statistician would have tighter confidence intervals and would be able to say that there is a 98% chance of a 6 week PFS improvement (maybe a 99.5% chance of a 4 week difference). Would you unblind now?? We do not know the constraints or flexibility built into the H+N SPA but this is the gist of the decision making process.

Once the company makes the decision to unblind, they will have to live with the results as they stand. They direct the CRO to break the blind; the unblinded data comes to the statistician and two curves are generated and compared. If the difference between the two curves is sufficient (ie: >70% likelihood of success with 400+ patients enrolled), the SPA allows for continuation of the trial. Anything less.....the trial is discontinued on the basis of futility.

I don't know how much flexibility the SPA allows for......no matter what, the survival data are rapidly maturing at this point. The PFS data determine the go vs. no-go decision but what happens if the raw survival data are ready to report? Not much interpretation on those numbers and, at this point, more than half of the ITT population has died. If the trial were unblinded today, there would be very, very strong survival data already. Survival trumps PFS but what would the FDA say if the PFS is weak but the right side of the survival curve is strong?

It is getting interesting.....the screws are turning tighter.

For most of the biotechs that I have followed over the years, delays in data release portends bad results. I hope that this trend does not hold true for the ONCY H+N data!! No matter what, the lifespan of this group of patients enforces the duration of the trial. In October (6 weeks from now), 6m survival stats are available on all 80 patients. Effectively, the statistical package would be complete. Not much ducking that milestone event!!

Dog days of August!!!

Cheers, Geneman

ONCY Ph III interim results: ONCY has not run a randomized trial in H+N until this SPA Ph III. The decision to move into the Ph III was based on a group of different studies done by different PIs. A Ph I intra-tumoral study that showed safe administration but, importantly, showed dramatic resolution of H+N cancers both in the field of the injection and distally. A Ph I dose escalation trial with radiation showed similar results; a Ph 1 dose escalation trial with combination chemotherapy showed dramatic resolution of primary and metastatic lesions in a substantial number of patients. Two separate non-randomized Ph II trials in the UK and the US showed a RECIST response rate of 30-40% and a dramatically lengthened TTP. All of these studies were completed in end-stage, heavily pre-treated patients with metastatic H+N cancer. Typically, the median PFS would be about 8 weeks (1 evaluation) and the median survival would be about 18 weeks. You can argue the numbers based on the patient entry characteristics but these numbers are certainly very close to what has been experienced for the last 30 years of minimal improvement in therapy for this indication. The two Ph II studies independently showed a RECIST response rate that was 5X expected and the PFS was doubled. Hard to comment on KM curves in a non-randomized study, but the overall survivals were pushed far to the right with a very significant portion of the curve persisting beyond 1 year.

With this information in hand, ONCY went to the FDA and negotiated the current SPA and the adaptive stats. Indeed they come to this juncture with no randomized data but they have spent many years assembling the clinical signal for H+N. They have not come to this Ph III decision by running a single Ph II trial out of the blue and then pushing on to a Ph III hoping for a miracle. No doubt that it would have been preferable to have the randomized data but other features of the clinical responses have also been considered. I would not put this study into the same basket as all of the other crappy Ph III trials of the me too drugs. More sweat and tears into this one.

We can only wait and see.......que sera, sera.

Cheers, Geneman

ONCY H+N Ph III trial: A bit of a contradiction of terms.....if these small companies had a anti-cancer drug that was "proven", they would not be a small company!! Oncolytic viruses are maturing as a paradigm for cancer treatment. As with all of the other alternatives to surgery, chemo and radiation, the road to success is littered with failures and heady promises. Academic institutions as well as biotech companies have forged steps towards a clinically viable oncolytic viral product; some have proved clumsy and some elegant. It may be prudent to check in every couple of years to review progress in the field. Any success in this area would open up a new option for direct treatment, adjuvant therapy, management of cancer stem cells and the potential for forcing immunologic recognition of cancer cells. Nothing happens quickly.......each of the small oncolyic virus companies has been developed on the backs of "failed" projects but incremental progress.

The current successful clinical programs have a few things in common; virtually no side effects, cancer tropisms based on major biological drivers of cancer, a broad range of applicability (not specific to cancer type)........the recipe for "personalized therapy" rather than just a perfunctory comment at the end of an FDA proposal. There are currently ~ 1000 clinical trials ongoing in oncology.....the vast majority are for a small number of indications....the vast majority are "me, too" drugs aimed at expanding current labels. Blockbusters do not come from those trials.

Viral treatments seek out a biological target....not a cancer type. Investment evaluations of companies promoting oncolytic viruses require a different process as the values of the companies are related to the prevalence of the targets, effectiveness of delivery and subsequent clinical effect. The value is not cancer-type specific but rather specific to targeted delivery and sustaining clinical effect.....proven over a range of cancers that express the target marker.

If the adaptive stats for the first phase of the ONCY Ph III trial support continuation of enrolment, there will be >70% chance of statistically significant survival advantage. It would also provide validation of potential for the treatment of other RAS+ tumors. Randomized trials are ongoing for Pancreatic, Breast, Prostate, SCLC, Squamous lung, colon, ovarian. Even a sniff of these markets would be transformational for Oncolytics Biotech. High risk but too much potential to dismiss off-hand.

All IMHO.....cheers, Geneman

I have followed ONCY since IPO more than 12y ago. They are employing an unmodified orphan virus (Reovirus) that exhibits a tropism for RAS+ cells. As with all oncolytic viruses, the anti-tumor activity comes from exploiting a cancer "driver", in this case RAS. All preclinical studies have shown that Reovirus effectively kills RAS+ cancer cells. More than 2/3 of metastatic solid tumors are either RAS mutated or RAS activity amplified. Phase 1 clinical trials showed no safety concerns and no MTD. With direct tumor injection, numerous examples of tumor regression were noted in a broad range of late stage, extensively treated patients with metastatic cancers (locally and distally).

A group of PhII studies were completed in metastatic cancers. One group involved direct injection of superficial metastatic lesions and showed anti-tumor effect. One group of Ph II studies involved IV administration of Reovirus (with SOC chemotherapy) to heavily pretreated patients with metastatic cancer. 70-90% of patients had clinical responses, but importantly, some of the patients with Head and Neck cancer exhibited extensive responses and prolonged survival. This work spawned two further Ph II H+N trials in heavily pre-treated patients that identified a clinical benefit rate in the range of 70-80% and a RECIST response rate of 30-40% (total patients ~ 33; expected response rate of 5%). Importantly, progression free survival was doubled in both of these separate trials (in fact, PFS was equal to expectations of OS). Long term followup of these patients have identified a rightward shift of the KM curves with an impression of a survival advantage (Ph II trials). Further preclinical and clinical work led to the identification of a synergistic effect between Reovirus and a broad range of chemotherapies.

These preclinical and clinical trials led to an FDA sponsored PH III SPA utilizing an adaptive statistical analysis. At 80 patients (40/40), an analysis of PFS (by RECIST) will indicate a go/no go for continuing the Ph III trial. The 80th patient was enrolled at the very end of March and the PFS evaluation occurs at 12 weeks. The PFS data on the entire 80 patient cadre will be available in the very near future. The trial will only continue if there is an estimated 70%+ likelihood of eventual success for the entire Ph III trial. That is where the H+N trials stand.

In addition to the H+N trial, the company has randomized trials approved or enrolling for Pancreatic, Colon, Breast, Prostate, Ovarian, Squamous Lung, NSCLC. Additional non-randomized trials are ongoing with multiple myeloma, Pediatric sarcomas and colon cancer. Earlier evaluations of IV administration of Reolysin plus chemotherapy in each of these indications has established consistent evidence of anti-cancer activity and clinical benefit rates of 70-90% for all of the cancers mentioned above. Many of these trials are essentially fully sponsored by large academic institutions and the company has about 2 years of money available based on the current burn.

Bottom line for ONCY involves proving that Reovirus plus chemotherapy improves overall survival for patients with advanced cancers. The first test of concept comes with the interim PFS results of the 80 patient, randomized Ph III trial for advanced H+N cancer. If these results are good, the chance of success for the entire H+N trial is excellent and the proof of concept would suggest that combination chemotherapy plus Reovirus would work in other cancers expressing RAS. If indeed the interim H+N trial proves futile, the shareprice will take a hit and the chances of eventual success will be decimated.

Not really a one-trick pony in the conventional sense but the company is certainly hanging it's hat on exploiting the RAS pathway......they have many trials ongoing and many irons in the fire. If they can show success for any single clinical indication, they are off to the races. With each failure, they diminish the chance of success. If they are successful, treating RAS+ cancers would be a multi-billion dollar market........not much else to say, really. Soon we will see.

cheers, Geneman

Eagle: A small point but....when the company has discussed the fully enrolled IMPACT study, I do not remember them speaking about an interim evaluation of any measures of futility. Tests of futility are common as you move through the enrollment of trials (ie Novacea), where the DSMB can stop a trial after an unfavorable risk assessment at a certain enrollment number.

Once the trial is fully enrolled and has completed the DSMB requirements, I don't know if measures of futility are incorporated in the interim analysis. Do others remember any company discussion on this topic?

cheers, Geneman

Stuck: I am the same guy, just older. I still follow ONCY closely and have been involved since the IPO. Mostly lurk unless I think I can add something pertinent from my specialty.

Cheers, Geneman

Biomund: without getting too complicated, the nature or "temperament" of each form of cancer is different (and each person's cancer is distinct). For example, Ovarian cancer, pancreatic cancer, some sarcomas develop the ability to metastasize very early in their evolution while others (prostate, colon, basal cell, glioblastoma) develop the machinery to spread much later. Rancherho and I are talking about the same thing except he is talking about treating already metastasized disease and I am talking about the process from the initial abnormal cell line.

At some point, a dominant clone evolves from the original tumor and spreads. That clone evolves from the original site and then further evolves along a separate path. Many cancer clones self-destruct while others become more and more lethal. The lethal clones cloak themselves with immune protection, seek out nutrition in novel ways, learn to break down mechanical barriers between cells and organs and develop methods to turn down the natural machinery that leads to naturally programmed cell death.

When we treat an early or middle stage cancer, some times the chemotherapy is sufficient to turn the tables on the cancer. Cancers are always in a life or death battle themselves.......they have to escape immune surveillance and they have to be able to live and proliferate without outgrowing their means. Chemotherapy can tip the balance by directly killing the cancer cells but also alerts the immune system to the invading neoplasm by forcing the cancer into repair mode (allowing for immune detection). If the balance is tipped sufficiently for the body eliminate the cancer, the patient may become cancer-free.

We end up getting our first indication of metastatic disease when the lesions become radiologically visible but the progenitors of this end-stage process usually start the process years before. Chemotherapy fails when clones with metastatic potential are not eliminated....... whether they have spread or whether they are still contained in the original tumor mass. Considerable interest in "cancer stem cells" follows along this line. If you can't eliminate the ultimate proliferative source of the cancer, it doesn't matter that you destroy the bulk of the cancer cells. There is a constant source of malignant cells that are evolving and mutating as treatment progresses. If you can't destroy this ultimate fountain of malignant cells, it is inevitable that the cancer will evolve to resistance and overwhelm the patient.

The bottom line is that the majority of cancer deaths come from the eventual evolution of the cells to a lethal metastatic clone. Slowing progression does not necessarily improve overall survival and may not even extend the length of a person's life. If you get at the cancer before the genetic events lead to metastatic potential, there is a reasonable chance of a "cure".

Cheers, Geneman

Biomund: A tumor is a mixture of cells that vary in their genetic nastiness. If there are 1000 cells in the tumor, 100 of these have a genetic makeup that will eventually produce the metastatic spread of the original cancer. We treat the 1000 cells with chemotherapy and kill off 500 of the weaker cancer cells (reducing the tumor burden by 50%) but we are also strongly selecting for the resistant cancer cells to proliferate. By killing off the weaker cancer cells, we are actually improving the local environment for the nastiest cells as they are not inhibited by typical cell-cell interactions and there is less competition for blood flow, nutrition and other substrate. Most of the chemotherapies place a strong selection pressure on the worst of the cancer cells and strongly selects for aggressive, chemo resistant clones of cancer. It is these clones that metastasize so rapidly at the end of the patient's illness. They are the result of the artificial selection pressure produced by chemo.

What we see clinically is a short term effect on tumor bulk (reduce the visible amount of cancer by weeding out the weaker cancer cells). This is translated as "an improvement" in progression free survival. Once the weaker cells are killed off, the patient is left with the nastiest of the cells that have been untouched by the chemo except selected for more aggressive traits. These cells are now chemo-resistant and have very well developed growth characteristics. They rapidly overwhelm the patient.

These are common situations. Our treatment kills the weaker cancer cells but is unable to kill the cells that are destined to metastasize. Unwittingly, we provide a better environment for the worst of the cells which then run the show in the second half of treatment. Clinically, things can look quite good as the chemo devastates most of the cancer cells at the beginning of treatment but it is the cells that have metastatic potential that have to be killed. Once the resistant cells get control, the clinical course accelerates to death.

Thus, an improvement in progression-free survival may not be associated with any overall survival benefit. That is not to say that improving the length of time to symptoms is not an important goal but let's not confuse PFS as an accurate surrogate for overall survival.

These types of findings are seen in Radiation therapy and many forms of therapies for solid tumors. Pt therapy for Ovarian cancer is a great example.

cheers, Geneman