Laboratory detection of primary and acquired drug resistance in human lymphatic neoplasms 1986 Cancer Treatment Reports Weisenthal et alFebruary 14th, 2013
I am interested in the status of culturing tumor cells to refine chemotherapy from an investment/legal perspective. I have a few questions:
1. I do not see any entries on this site since 2010. Is the site still active?
2. Larry states that no money is to be made by labs that could or would perform the lab work. On what basis is this statement made?
3. Has the FDA moved to regulate such labs to date and if not what seems to be the likely outcome on this question?
4. How is it possible that patients who want these tests could not pay to make them available?
5. In several cases I have witnessed friends fighting dancer and engaging in chemotherapy and I have asked how the selection of chemotherapeutic agents is made. Most recently the response was they just try some and hope they work. I have only a limited scientific background, but have a good education in business and law. However, I think that I can understand this. I recently took a microbiology class, and in the lab did a Kirby Bauer Assay — the infectious disease equivalent to what is proposed here for cancer.
My understanding is that the Kirby Bauer testing a culture against different antibiotics dates back to the 40s or 50s.
6. Sorry this a bit long winded but I may have even more as follow up.
Administrator’s note: For reply to the above queries, please click on “about CancerTest.org,” under “Pages,” top-right margin of this page, and scroll down.
The following is a bit off the topic of cancer tests, but it goes along with the general theme of individualizing patient treatment.
In yet another long term follow up of the massive Women’s Health Initiative study, which included a randomization between placebo and hormone replacement therapy (“HRT,” with estrogen + progesterone), an increased incidence of breast cancer and increased breast cancer deaths are being reported.
What is being (erroneously) disseminated in the media is the following message: “Not only does prolonged use of hormone replacement therapy raise the risk of breast cancer, new research finds, but it also ups the risk for more severe forms of the disease and increases a woman’s chances of dying.”
This most recent WHI paper only looks at (1) breast cancer mortality and (2) all cause mortality after a diagnosis of breast cancer. It does not report all cause mortality! Therefore, it cannot be stated that HRT “increases a woman’s chances of dying.”
An earlier study published by the same authors showed a slight (non-significant) reduction in all cause mortality with HRT and a significantly decreased incidence of colon cancer and hip fractures.
The risk of death following hip fractures has been stated to exceed the risk of death following breast cancer in post menopausal women.
I watched and listened to the lead author (Dr. Rowan Chlebowski, who is a medical oncologist with the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center) on the PBS News Hour on October 19, 2010, and I read the JAMA editorial which accompanied the Chlebowski paper and I felt that both exhibited much greater certitude in discouraging HRT use than the data support.
Risks and benefits must be individualized. Thin post menopausal women, with physically active lifestyles, non-hyperdense breasts, low to negligible alcohol consumption, lack of family history, negative mammograms, low fat diets, no tobacco use, low risk of coronary artery disease, and severe osteopenia are at high risk for high lethality hip fractures, but at low risk for breast cancer, lung cancer, and thromboembolic disorders. Might not the risk benefit ratio of lower dose, transdermal HRT be favorable?
I just use the above as an example. The absolute risk magnitude of breast cancer attributable to HRT remains very low, and there other threats to health and happiness in post-menopausal women beyond breast cancer.
I understand that a continuing series of articles from this study is planned for the future. Were I a reviewer, I’d demand that all cause mortality data be published with each and every one of these forthcoming studies.
In an earlier, previously-reported study from the same authors, the risk of non-small cell lung cancer was cited as a possible complication of HRT. But the absolute magnitude of risk was very small, and was not close to being significant in the case of never smokers. As noted above, yet another prior study had shown a significant decrease in the incidence of colon cancer, in women receiving HRT, compared to placebo. Along with the substantial reduction in hip fractures.
Yet study authors, editorialists, and especially the media are now making it appear that prescription of HRT to post-menopausal women is virtually tantamount to malpractice. I strongly disagree with this position. HRT has a risk benefit ratio, along with everything else in medicine. And this risk benefit ratio is hugely different in different subsets of patients.
Which is why therapy should be individualized and why broad, one size fits all pronouncements and messages should be discouraged.
- Larry Weisenthal
Oncotech is — or was — an American laboratory providing individualized tumor response testing (ITRT) as a service to patients and physicians since the mid-1980s. It was co-founded by Robert Nagourney and I. We each left the company in the early 1990s, over disagreements with the controlling investors (4 venture capital companies) over the management and directions of the company. I remained supportive of the company, over the years, and played an important role in securing and, later, retaining reimbursement by Medicare for their services. Robert and I each started our own small private laboratories to offer related cell culture testing services.
Oncotech continued operations as a privately-held, venture-capital controlled company until February of 2008, when it was acquired (purchased) by a Danish biotechnology company called Exiqon, Inc. for $45 million (US) in Exiqon securities.
Exiqon replaced the Oncotech CEO and installed its own management team, continuing to operate Oncotech as a wholly-owned subsidiary, with a business model centered around providing ITRT on a (US) national basis — importantly to Medicare patients.
In the case of my own laboratory, we opted out of Medicare, effective July 1. 2008, because the reimbursements received from Medicare did not cover our costs of providing our services.
Exiqon Oncotech, however, depended on Medicare reimbursement to support its business model. In the USA, Medicare coverage decisions for many types of medical services are made at the regional level, by the private insurance companies with which Medicare contracts to administer services to Medicare beneficiaries (most prominently, patients 65 years of age and older). Previous Medicare contractors for California made the determination that ITRT qualified as a Medicare covered service. These included the TransAmerica and National Heritage Insurance companies. Most recently, an insurance company called Palmetto was awarded the contract to administer Medicare services for California. Palmetto made the decision to discontinue Medicare payment for ITRT in California.
Last week, Exiqon Oncotech announced that it was discontinuing operations, because of the withdrawal of Medicare reimbursement for its services. This was an entirely understandable, if regrettable, decision. What was in no way understandable — or defendable, for that matter — was the way that they ceased operations.
Exiqon Oncotech sent out notifications to its client physicians that it was ceasing operations, virtually immediately. On a single day this past week, they received two dozen specimens from human tumor biopsies via FedEx and other couriers. All of these specimens were simply sent back to the hospitals and clinics which sent the specimens. Physicians were told that there were no other laboratories who could perform the tests requested.
While it is true that no other American laboratories have chosen to utilize Exiqon Oncotech’s non-proprietary technology for ITRT, it was well known to Exiqon Oncotech that there are a number of highly experienced, well qualified, well-published American laboratories which provide this service, utilizing different, but at least comparably valid, technologies.
In my long experience in this field, I well remember two previous, investor-backed, clinical laboratory companies which provided ITRT as a service to patients, only to make the decision that their business models were no longer viable. These companies were (1) Analytical Biosystems and (2) NuOncology Laboratories. When these latter companies ceased operations they (a) did so in an orderly fashion, giving their clients adequate advance warning and winding down operations at a pace which enabled them to provide testing for those patients and physicians who had already planned and depended upon receiving these services, and (b) these companies were open and helpful in providing their former client physicians with contact information for other laboratories within the US which continued to provide ITRT services.
In the case of Exiqon Oncotech’s two dozen tumor specimens simply marked “return to sender,” I can scarcely imagine anything more irresponsible. In many of those cases, doubtless the physicians and/or surgeons discussed in advance with their patients the importance of sending their biopsies for ITRT. In some cases, the surgical procedure may have been performed primarily for the purpose of ITRT. In other cases, the patients were doubtless comforted by knowing that this testing was to be performed.
Business is business, but, at a certain point, business is also about people, and cancer business is, or should be, about cancer patients.
I am saddened by the shuttering of Oncotech’s doors, 25 years after its founding, and I am ashamed at the way in which those doors were apparently shuttered.
It should be noted that the Medicare contractor for the state of Pennsylvania continues to provide coverage for ITRT and that there is an experienced laboratory in Pennsylvania (Precision Therapeutics) which both provides ITRT and accepts Medicare reimbursement as payment in full. California laboratories continuing to provide ITRT (without Medicare reimbursement, possibly requiring patient payment for services) include Rational Therapeutics, Anticancer, Inc., and my own laboratory.
- Larry Weisenthal 12-June-2010
Follow-up: an earlier blogpost by an Exiqon Oncotech employee provides independent confirmation of the above.
I participate in an international discussion group relating to individualized tumor response testing (ITRT), otherwise known as cell culture drug response testing (CCDRT). Most recently, the topic of ITRT/CCDRT in non-Hodgkin’s lymphoma (NHL) was raised. One European group utilizes the ATP endpoint. Another European group utilizes a modification of the DISC endpoint (dye exclusion by living cells, in a system capable of selectively identifying the living cells as being either neoplastic or normal). Both ATP and DISC endpoints are based on cell kill/cell death (as opposed to cell proliferation/DNA synthesis, which is the other major ITRT/CCDRT endpoint). The DISC endpoint is capable of discriminating between drug effects of neoplastic versus normal cells, present in the same cell culture, while the ATP is not selective for neoplastic cells versus normal cells.
Generally speaking, the results of cell death endpoints agree with each other pretty well, as long as the cell population being measured is predominately the cell population of interest (in this case, tumor or neoplastic cells). This should not be surprising — after all, a dead cell is a dead cell. The problem comes when there are appreciable numbers of “contaminating” normal/non-neoplastic cells present. In these cases, endpoints which are not specific for tumor cells may produce skewed results.
The table below shows solid tumor correlation coefficients, comparing DISC (“specific for tumor cells”) and MTT (not “specific for tumor cells”) endpoints. These data come from studies in which individual tumors were simultaneously tested in each endpoint, after being cultured in precisely the same conditions, for precisely the same period of time. It can be seen that, in the case of the drug melphalan, when there are greater than 40% tumor cells with solid tumors, the results of DISC and MTT endpoints agree quite well. There were relatively few cases in which specimens with fewer than 40% tumor cells were tested with the non-tumor-selective (MTT) endpoint (because of advance knowledge that, in such specimens, the MTT endpoint was not reliably discriminatory for tumor cells). In the few such cases tested, the MTT/DISC correlations were not very good (r=0.51, r2=0.26).
Comparison between MTT and DISC results for melphalan in solid tumors as a function of percentage of total viable cells which were tumor/neoplastic cells postculture:
TIn contrast, in the case of melphalan in non-Hodgkin’s lymphoma/chronic lymphocytic leukemia, there was progressively serious skewing of MTT results by normal cells, as the post-culture percentage of neoplastic cells dropped below 95%:
The following two scattergrams show similar data graphically (but with solid tumor data limited to ovarian cancer, to simplify the comparisons):
These artifactual results with the metabolic endpoint can seriously comprise the biological validity of the assay results, as shown in the following two graphs.
These data analyses are based on the principle that chemonaive tumors (i.e. from previously-untreated patients) are well known to be more drug sensitive/less drug resistant than are non-chemonaive tumors (i.e. from previously-treated patients):
In the above graph, from the ovarian cancer dataset, it can be seen that, in BOTH DISC and MTT endpoints, specimens from previously-treated patients were significantly more resistant to melphalan than were specimens from chemonaive/previously-untreated patients.
However, there were far different results with the NHL/CLL dataset:
In the case of CLL/NHL, where the effect of normal cells skewing the results of the non-tumor-cell-discriminatory MTT endpoint is much greater, the greater chemosensitivity for specimens from untreated patients was confirmed with the (selective) DISC endpoint, but was not observed with the (non-selective) MTT endpoint.
The problem in NHL/CLL is that the metabolic activity of the neoplastic cells (on a per cell basis) can be low, relative to the metabolic activity of normal cells (e.g. macrophages, cell culture transformed normal T-lymphocytes, etc.). Thus, the normal cells typically present in specimens from lymphatic neoplasms may skew/disort the cell death estimates to a much greater extent than in the case of the typical solid tumors. Thus, results of non-discriminatory endpoints (e.g. MTT, ATP) must be interpreted with caution, in the case of lymphatic neoplasms.
We have similar data in the case of acute non-lymphocytic leukemia (skewing of results by normal cells with non-selective endpoints). We do not have sufficient numbers of datapoints in the case of acute lymphoblastic leukemia to make these comparisons.
It is obvious that non-selective endpoints will have very little utility in neoplasms such as Hodgkin’s Disease and multiple myeloma, where most specimens have very large numbers of “contaminating” normal cells.
33 minute lecture on functional profiling of human cancer, using cell culture drug resistance testing on fresh human tumor specimens obtained by surgical biopsy. This lecture was given at Charite University Medical Center in Berlin, Germany on March 19, 2009 by Larry Weisenthal, MD PhD. The audience consisted primarily of oncologists and surgeons working in the field of gynecologic oncology. Thanks to Dr. Frank Kischkel, TherapySelect GmbH & Co. KG, Heidelberg, Germany
My colleagues and I are working on an updated format for the Human Tumor Assay Journal, which now contains an atlas of fresh human tumors in short term suspension culture (click on Fresh Human Tumor Cell Culture Atlas illustrating examples of (1) the appearance of the fresh tumors immediately following scissor mincing and digestion with collagenase/DNAse, (2) appearance of “control” (cultured without drugs) tumor cells, following 96 hours of suspension culture, in anchorage-independent conditions, (3) appearance of cells when cultured with an “effective”/”active” drug, and (4) appearance of cells when cultured with an “ineffective”/”inactive” drug.
The atlas is a work in progress, but it now has sufficient numbers of examples of different classes of tumors that I hope it will be useful to workers in this field.
Comments and suggestions are welcome.
- Larry Weisenthal/Huntington Beach, CA firstname.lastname@example.org
I’m currently attending the 2009 American Society of Clinical Oncology (ASCO) breast cancer symposium, in San Francisco.
The Keynote Address (by Martine PIccart-Gebhart of the Jules Bordet Institute) was very relevant to Individualized Tumor Response Testing (ITRT). The speaker made the point that only 8% of new drugs entering Phase I trials ever make it to marketing and that this percentage is even lower for cancer drugs, because “current drug testing is inefficient, with many drugs failing late in development,” with “these expensive failures” owing, in large measure, to “ineffective drugs” and “poor patient selection (i.e, lack of prognostic and predictive markers for response to therapy).”
The speaker went on to note that “little progress has been made in identifying which therapeutic strategies are likely to be effective for individual patients.” The speaker concluded that “identifying markers that can predict response to a particular drug remains a great challenge.”
To my knowledge, there is absolutely nothing being presented at this meeting which reports any progress at all in drug selection through the use of molecular profiling. Perhaps I’ve missed something. There is another half day remaining.
When microarrays and high throughput RT-PCR emerged some years back, I’d have predicted quite a bit of progress by now. Instead, there were a couple of early clinical studies, and virtually no follow up by now. Certainly, the sum total of the cell culture-based literature is vastly superior, taken as a whole, to the sum total of the molecular profiling-based literature for drug selection. One would think that there would be at least equal interest in cell culture-based approaches. Sadly, no.
I presented what I think was an important study in a poster session. It attracted virtually no interest. I’d like to briefly go through the most important points here. I’d be very interested in feedback, comments, and/or criticism, preferably on this blog, but, if preferred, as a private email: email@example.com
The problem I addressed is that of so-called “triple negative” breast cancer (TNBC), which is: Estrogen Receptor Negative (ER-), Progesterone Receptor Negative (PR-), and Her2 Negative (H2-).
When breast cancer presents as locally advanced disease, it is customarily treated with neoadjuvant (preoperative) chemotherapy, followed by definitive surgery. At the time of surgery, the specimen is assessed to determine if all visible tumor has been destroyed by chemotherapy. When this happens, it is said to be a “pathological complete response” (pCR). The Kaplan-Meier curves below show survival in Non-TNBC and TNBC, as a function of whether or not preoperative chemotherapy produced a pCR.
In the figure below, the yellow line is the survival for non-TNBC patients who achieved a pCR; the blue dashed line is the survival of TNBC patients who achieved a pCR; the black dashed line is for non-TNBC who did not achieve a pCR; and the red dashed line is for TNBC patients who did not achieve a pCR.
These data show that obtaining a pCR is everything. Get a pCR, and the survival is excellent. Don’t get a pCR and the survival, especially for TNBC patients, is very poor.
So the issue is this: what can we do to improve the pCR rate in TNBC?
I began by going through our database of breast cancer cell culture assays (using cell death endpoints) and trying to see if there were any drugs which appeared to be uniquely active in TNBC vs non-TNBC. Here’s a representation of what I found:
The horizontal bars show percent control cell survival for drug exposed cultures. The shorter the bar, the more active the drug. Error bars represent 95% confidence limits. These are representative data for a few of the more important drugs.
Essentially, there are no major differences between the activity of most drugs in TNBC vs non-TNBC, with one glaring exception: cisplatin, which was dramatically more active in TNBC than in non-TNBC.
I went on to present a lot of data further dissecting which specific markers were most associated with TNBC sensitivity to cisplatin. These data will shortly appear on the ASCO website, when they post slide presentations from the 2009 Breast Cancer Symposium. But the following were the most important “take home” messages:
Major markers for platinum sensitivity in breast cancer were:
1. Estrogen Receptor negativity
2. Bloom-Richardson (Nottingham) score of 9/9 (i.e. very poorly differentiated tumors.
Minor markers for platinum sensitivity in breast cancer were:
1. Her2 negativity
2. Progesterone receptor negativity
The following puts the findings into a useful perspective:
These data compare TNBC to other types of tumors. It’s known that renal cell carcinomas are very resistant to cisplatin (less than 10% response rate), and that is reflected by the cell culture (cell death endpoint) data. It’s known that previously-untreated, poorly differentiated ovarian cancers tend to be very sensitive to cisplatin (70% response rate), and that’s also reflected by the cell culture data. When ovarian cancer patients relapse soon (0 to 6 months) after discontinuation of chemotherapy, they have only a 25% response rate to re-treatment with platinum. When ovarian cancer patients relapse greater than 6 months following discontinuation of chemotherapy, they have a 50% response rate to re-treatment with platinum. These clinical findings are also nicely recapitulated by the cell culture assay data.
Now, breast cancers which are either estrogen receptor positive and/or more than very poortly differentiated (Bloom Richardson score of 4 to eight) tend to be even more resistant to cisplatin than are previously treated ovarian cancer which relapse soon (0 to 6 months) after discontinuation of chemotherapy. In contrast, Triple Negative Breast Cancers tend to be as sensitive or more sensitive (especially when also Bloom Richardson 9/9) to cisplatin than are previously-untreated, poorly-differentiated ovarian cancers.
I think that these data clearly show the utility of cell culture assays in “targeting” chemotherapy to patient sub-groups who are most likely to benefit from treatment with given individual drugs. It’s hard to see how “molecular” profiling tests could have produced similar insights.
The following were my summary conclusions, comparing cell culture profiling versus “molecular” profiling:
So the question is this: Why is there absolutely no interest in cell culture tests?
- Larry Weisenthal/Huntington Beach, CA
A just-published study in ovarian cancer raises the question of the distinction, if any, between “chemosensitivity” and “chemoresistance” (or “drug resistance”). It has been my position, for a long time, that these distinctions are largely semantic and not of useful clinical relevance. Resistance is the relative absence of sensitivity and sensitivity is the relative absence of resistance.
A number of authors have tried to claim superiority for one type of assay over another, when, in reality, both assays are attempting to make the same distinction — which drugs are the more promising and which are the less promising for a given clinical application? One good example of this attempt to claim the semantic high ground is the very complicated argument made by John Fruehauf and Dave Alberts in a letter published in the Journal of Clinical Oncology. (In Vitro Drug Resistance Versus Chemosensitivity: Two Sides of Different Coins, DOI: 10.1200/JCO.2005.05.281).
The letter by Fruehauf and Alberts is ironic in the context of the just-published paper by Matsuo, K. et al. (Low drug resistance to both platinum and taxane chemotherapy on an in-vitro drug resistance assay predicts improved survival in patients with advanced epithelial ovarian, fallopian, and peritoneal cancer. Int. J Cancer, 2009 DOI: 10.1002/ijc.24654). Fruehauf and Alberts extol the virtues of the drug resistance side of the coin, specifically referring to the soft agarose, tritiated thymidine assay of Kern, with statistical definitions of drug resistance originated by me (Kern and Weisenthal, JNCI, 1990). Yet both the Matsuo study (above) and another recent study (just presented at the June, 2009 ASCO meeting) show no useful correlation between the “extreme drug resistance” endpoint and any clinical outcome in ovarian cancer, while the Matsuo study shows highly (and independently) significant correlations between the “low drug resistance” (which could just as easily be called “chemosensitive”) endpoint with both progression-free and overall survival.
Correlations between “Sensitive” vs “Resistant” cell death assay results and clinical response to chemotherapy in published studies
Several things are evident:
1. In all individual studies, patients treated with drugs classified as “sensitive” had a higher response rate than that for all the patients in each individual study.
2. In all individual studies, patients treated with drugs classified as “resistant” had a lower response rate than that for all the patients in each individual study.
3. In all individual studies, patients treated with drugs classified as “sensitive” had a MUCH high response rate than for patients treated with drugs classified as “resistant.”
4. Averaging up all of the studies, patients treated with drugs classified as “sensitive” had an 8-fold higher response rate than patients treated with drugs classified as “resistant.”
I think that all of the above data point to the fact that differences between “chemosensitivity” and “chemoresistance” are entirely semantic and that the proper role for these assays is to direct attention towards agents in the “sensitive” (or “low resistance”) group and away from agents in the “resistant” (or “low sensitivity” group).
- Larry Weisenthal/Huntington Beach, CA USA
Presented this morning at the American Association of Cancer Research meetings in Denver, Colorado, is an interesting study by Daniel Von Hoff and associates of the Phoenix-based Translational Genomics Research Institute (TGen).
From the TGen press release:
66 patients were treated at 9 different U.S. medical centers. All of the patients had previously experienced growth of their tumors while undergoing as many as two to six prior cancer treatments, including conventional chemotherapy.
However, after molecular profiling identified precise targets, new treatments were administered that resulted in patients experiencing significant periods of time when there was no progression of their cancer.
“This clinical trial was unique because patients acted as their own control,” said Dr. Von Hoff. “We compared each patient’s progression-free survival, following treatment based on molecular profiling, to how their tumors progressed under their prior treatment regimens, before molecular profiling.”
In a significant number of patients, the targeted treatments provided significantly longer periods when tumors did not progress, or even shrunk, said Dr. Von Hoff, who also is a Medical Director of US Oncology and a former Director of the Arizona Cancer Center at the University of Arizona.
He said this clinical trial demonstrated the value of personalized medicine, in which treatments are prescribed based on an individual’s specific genetic makeup. The type of drugs, dosages, their delivery and other treatment aspects – all are based on each patient’s individual medical needs.
Among the patients, 27 percent had breast cancer, 17 percent had colorectal cancer, 8 percent had ovarian cancer and 48 percent had cancers that were classified as miscellaneous.
Patients experienced varying levels of improvement. Among those with breast cancer, the period of progression-free survival increased for 44 percent of patients; for colorectal, 36 percent of patients; for ovarian, 20 percent of patients; and for miscellaneous cancers the improvement was seen in 16 percent of patients.
The molecular profiling for this research study was performed by Caris Diagnostics (Caris Dx) in Phoenix.
These results are the first in a series of studies in support of Target Now™, a commercially-available oncology testing service offered exclusively by Caris Dx. Target Now uses cutting-edge molecular profiling techniques, including both DNA microarray and immunohistochemical (IHC) analysis, to provide individualized information about a patient’s tumor as an aid to the treating oncologist.
The study was supported by a $5 million donation by a private philanthropist, apparently a cancer patient, as reported in the above press release.
This is a very interesting and innovative study design. It is very difficult (and horrendously expensive) to perform prospective, randomized trials. It is much simpler to use each patient as his/her own control, comparing results (progression-free survival) of the previous, empiric therapy with the “targeted” therapy. Even with the simplified design, however, this pilot study cost $5 million. The weaknesses are the often poor correlation of progression-free survival with overall survival and the subjectivity of “progression free survival” as a study endpoint.
Study details are eagerly awaited.
Edit April 20, 2009 16:13 GMT –>
The Von Hoff study abstract is now on American Association for Cancer Research Website.
Larry’s comments, based on data in study abstract:
Patients eligible had to have (1) clear disease progression on prior therapy and (2) received at least two prior lines of systemic chemotherapy. “Success” was defined as a time to progression (TTP) of at least 30% longer than the TTP of the most immediate prior therapy. A total of 18 patients (of 66) achieved this 30% improvement in time to progression.
An interesting question is what percentage of cancer patients in general have increased times to progression with subsequent cycles of empiric chemotherapy, compared to the prior empiric therapy. As I write this, I don’t know if there are any published data on this. If anyone is aware of whether or not these data exist, I’d appreciate knowing about it. Either respond to this blog post (requires easy registration) or send me a private email: firstname.lastname@example.org. Thanks!
An additional issue is the precision with which time to progression (TTP) with prior therapy was measured. With prospective clinical trials, using TTP as the primary endpoint, there is generally a protocol to standardize follow-up, with physical examination, laboratory tests, and radiographic tests being performed as standardized intervals, so that comparisons of TTP are meaningful. There would appear to be a problem with utilizing “historical” TTP on patients enrolled from the general oncology community, in which there is no standardization regarding the methodology for determining disease progression or the intervals at which these measurements are taking place. Additionally, we don’t know, from what is presented in the abstract, whether or not there was “blinded” assessment of TTP by outside auditors, or whether “historical” TTP was assessed and reported by the referring oncologists who enrolled the patients onto the trial.