Recently in Oncology Category
A big HT to the WSJ Health Blog for showcasing this intriguing study in Health Affairs. Against the otherwise commonsensical preference for screening colonoscopy (to prevent and detect colorectal cancer), researchers at RTI International showed that yearly testing for fecal occult-blood leads to more life years saved. The result held even when adherence to CRC screening guidelines dropped to 40% and follow-up compliance was only 65%.
The context of the study was a fixed budget for a CRC-screening program ($1 million), and the assumed costs for guaiac testing and colonoscopy were $23 and $699, respectively. (Although the Healthcare Blue Book price for colonoscopy [no biopsy] is much higher, at $1658.) Consequently fecal occult-blood tests allowed the hypothetical program to screen more individuals and lead to a greater number of life-years gained.
The authors warned that the study only assessed life-years gained, not quality-adjusted life years (QALY), and that the test selection was made in the context of a fixed budget. "If there were no budget constraints," they wrote, "a different screening test might be preferable."
But really: When are there no budget constraints?
Addendum: At the WSJ Health Blog, one commenter raised the issue that the authors only assessed a hypothetical population-based screening program. The results do not necessarily indicate that fecal occult-blood tests are preferable screening tools for individuals who are at high risk for CRC (eg, people with Crohn disease or a family history of CRC).
Photo of Olympus standard video colonoscope: price, $3500. (Avoiding Olympus standard video colonoscope: priceless.)
Just as an astronomical white count is not an entity unto itself but a marker of a serious underlying disorder, like leukemia, so a big lie on a CV is an indicator of a grave underlying problem, like sociopathy.
Faculty members at the Duke Institute for Genome Sciences and Policy are learning this lesson the hard way thanks to the failure of someone at Duke to perform the basic HR duty of vetting Anil Potti's curriculum vitae 7 years ago. Potti, who was hired in 2003 as a physician-researcher by Duke, falsely claimed that he was a Rhodes Scholar on scientific grant proposals, according to a recent expose by Paul Goldberg in The Cancer Letter. That's a big lie and one suggesting that other big lies are possible, if not probable. Taking this very cue, Goldberg then questioned the integrity of Potti's research at Duke and found that 2 biostatisticians at M. D. Anderson discovered "a series of errors," including mislabeling errors, in a seminal article by Potti and others.
Consequently the biggest victim of Duke's remote HR lapse: cancer patients who enrolled in clinical trials, which were based on Potti's questionable work. According to the NYT, these trials have now been suspended (after stuttering efforts by Duke officials to reopen them, reported Goldberg). News coverage can also be found at NPR's Shots blog.
For yucks or groans, I performed a quick PubMed search: "A Potti" is the coauthor of 48 articles that were published within the last 5 years. Potti's articles appeared in, for example, PNAS, JAMA, JCO, PLoS One, Lancet Oncology, Nature Medicine, and the NEJM.
Photo of Anil Potti from Duke Institute for Genome Sciences and Policy.
10/24/10 addendum: As the AP reported yesterday, Lancet Oncology editor David Collingridge relayed an "expression of concern" from 15 European investigators who were coauthors with Potti and 3 other Duke researchers on a 2007 article in the journal. (The article validated the use of gene signatures to predict the response of breast cancers to neoadjuvant [perioperative] chemotherapy.) After the damning report from biostatisticians at M. D. Anderson about Potti's alleged errors in another article, the Lancet Oncology coauthors repeatedly attempted to contact their Duke colleagues, but they were ignored, wrote Collingridge.
The editor also revealed that "a large group of scientists" wrote to NCI director Harold Varmus on July 19th, expressing their concerns about the validity of a) Potti's cancer-treatment prediction models and b) 3 clinical trials that were based on these prediction models. Collingridge expressed his own concerns about the Lancet Oncology article given recent developments surrounding Potti. The journal has contacted the Duke coauthors—Anil Potti, Chaitanya Acharya, Sayan Mukherjee, and Joseph Nevins—and awaits their responses.
Dr. George Lundberg, MedPage's Editor at Large, is really excited about an article that was published in March in the Journal of Clinical Investigation. And he predicts big things for the article's authors, like a Nobel Prize.
The article, by California academicians and an employee at AntiCancer, Inc., describes how vasculogenesis* of irradiated tumors can be inhibited by an already approved drug, AMD3100, in a mouse model of glioblastoma multiforme—the deadliest of brain cancers.
AMD3100 is also known as plerixafor or Mozobil, which is owned by Genzyme. The injectable drug is currently indicated, in combination with G-CSF, to mobilize hematopoietic stem cells for autologous transplantation in patients with non-Hodgkin lymphoma or multiple myeloma. So human trials of the drug and uncontrolled case studies can begin, Lundberg argues, more or less immediately.
G-CSF = granulocyte-colony stimulating factor (eg, filgrastim [Neupogen; Amgen]).
* Which is distinguished from angiogenesis or "the sprouting and proliferation of endothelial cell from local vessels. The authors posit that tumor recurrence after radiation is largely mediated by vasculogenesis, the "colonization of circulating endothelial or other cells primarily from the bone marrow."
Photo of Ted Kennedy, who died last year of glioblastoma: Biographical Directory of the United States Congress.
A first-of-its-kind investigational vaccine prevents breast cancer in mice, according to a press release from Cleveland Clinic researchers. Results of their preclinical studies, which were published online Saturday in the journal Nature, lay the foundation for clinical development of the vaccine in women.
The new vaccine differs from the most notable cancer-preventing vaccine, Merck's Gardasil, in that it targets an autoantigen, alpha-lactalbumin, not a cancer-associated virus, like HPV. Alpha-lactalbumin is a breast-specific protein that is overexpressed in most breast cancers and during lactation, but not in normal breast tissue of nonlactating women. In transgenic mouse models of breast cancer, disease was prevented in all inoculated animals, while unvaccinated mice developed cancer. The vaccine also stymied the growth of existing tumors.
The excitement of the study's lead investigator, Vincent Tuohy, PhD, is palpable: "If it works in humans the way it works in mice, this will be monumental. We could eliminate breast cancer," he says in the press release. Tuohy proposes that the vaccine would be appropriate for women older than 40, when pregnancy (and lactation) is less likely and the risk of breast cancer rises.
Human trials of the vaccine may begin within the year, reports the Clinic.
HPV = human papillomavirus.
Mass screening or rational design? Malcolm Gladwell, the 10,000-hours guy with Leo Sayer's hair, examines the monumental barriers to finding effective treatments for cancer in the upcoming issue of the New Yorker.
Given the oppressive anti-pharma mood generated by mainstream media and Marcia Angell, it's refreshing to have Gladwell remind us—in a really entertaining way, no less—just how "boinking" hard it is to bring an effective and safe cancer therapy to market.
By using newly released data from Thomson Reuters (for 2010 and 2014) and EvaluatePharma (for 2016), a timeline graphic of the 7 drugs that are expected to remain within the top 10 best sellers is presented. Notably only 1 of the 7, Crestor, is a conventional pill.
Nilotinib (Tasigna; Novartis) may be poised to become first-line treatment for Philadelphia-chromosome-positive (Ph+) chronic myeloid leukemia (CML), like its sister drug imatinib (Gleevec; Novartis). In a company-funded, open-label, randomized head-to-head phase 3 study, nilotinib treatment produced significantly higher major molecular response* (MMR) rates at 1 year than imatinib in patients with newly diagnosed Ph+ CML. Results of the study were presented Tuesday at the annual meeting of the American Hematology Society (ASH) in New Orleans.
In addition, nilotinib treatment was associated with significantly higher rates of a complete cytogenetic response (CCyR)—the absence of Ph+ cells in bone marrow. All-important survival outcomes were apparently not included in the study, which is ongoing. (Long-term [ie, 60-month] data for first-line imatinib in Ph+ CML indicate an overall survival rate of 89%.)
|
Outcome |
Nilotinib |
Nilotinib |
Imatinib |
|
MMR | |||
|
3 mo, % |
9 |
5 |
1 |
|
6 mo, % |
33 |
30 |
12 |
|
12 mo, % |
44 |
43 |
22 |
|
Overall, % |
57 |
54 |
30 |
|
12 mo in high-risk pts, % |
41 |
32 |
17 |
|
Complete cytogenic response (CCyR) | |||
|
By 6 mo, % |
67 |
63 |
45 |
|
By 12 mo, % |
80 |
78 |
65 |
|
Est. rate of progression to accelerated phase/blast crisis at 12 mo, % |
<1 |
<1 |
4 |
|
Discontinuation due to adverse events or lab abnormalities, % |
7 |
11 |
9 |
Both nilotinib and imatinib are designed to inhibit the tyrosine-kinase portion (ie, the working end) of the abnormal fusion protein, bcl-abl, which is characteristic of Ph+ CML; but nilotinib is a more selective inhibitor than imatinib.
According to the WSJ, Gleevec, which is currently approved for the first-line treatment of Ph+ CML, generated $3.7 billion in sales last year for Novartis. But the drug's patent will expire in 2015. Nilotinib, 400 mg bid, is currently approved for the treatment of chronic- or accelerated-phase Ph+ CML that is resistant to imatinib. The FDA's Orange Book indicates that the patent on nilotinib will expire in 2023. Treatment with either drug costs more than $40,000 per year.
Last month, Kareem Abdul-Jabbar announced that he was diagnosed with Ph+ CML in December of 2008. It has been inferred here that he is or has been treated with imatinib.
N.B.—Trial name is Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients, abbreviated ENESTnd.
* Defined by the elimination of bone-marrow cells that carry the disease-defining bcr-abl fusion protein.
NBA legend Kareem Abdul-Jabbar, 62, has Philadelphia-chromosome-positive (Ph+) chronic myeloid leukemia (CML), according to numerous news sources. ABC News reports that Abdul-Jabbar was diagnosed with the disorder in December of last year. What treatment Jabbar has received to date is unclear; although the LA Times states that the disease is managed with "daily oral medication" (probably imatinib [Gleevec; Novartis]) and regular "blood analysis."
Here are some facts about CML and its treatment, according to the NCCN Clinical Practice Guidelines:
- CML accounts for 15% of adult leukemias. This year, an estimated 5050 cases will be diagnosed, and 470 will die of the disease.
- The median age of onset is 67 years.
- The disease is characterized by a translocation between chromosomes 9 and 22, resulting in the formation of the Philadelphia chromosome. The translocation results in a fusion gene, BCR-ABL, which is believed to play an important role in the development of CML. The fusion protein produced by BCR-ABL is an oncogene, with unregulated tyrosine-kinase (TK) activity.
- CML occurs in 3 phases: chronic, accelerated, and blast. CML is usually diagnosed in the chronic phase.
- Untreated CML will progress to advanced disease in 3-5 years.
- First-line treatment for chronic Ph+ CML is imatinib, a selective inhibitor of the TK portion of the bcr-abl fusion protein.
- Responses to the initial treatment of CML are monitored periodically (eg, every 3 months), by assessing bone marrow cytogenetics (ie, cytogenic response [CyR]) and transcript numbers of the BCR-ABL gene (ie, molecular response).
- Long-term data (median follow-up, 60 months) for first-line imatinib: complete CyR, 87%; overall survival, 89%.
- The most common high-grade toxicities with imatinib: neutropenia and thrombocytopenia. Rare cardiotoxicity has been reported with long-term therapy.
- The most common adverse events with imatinib: GI disturbances, edema, rash, and musculoskeletal complaints.
- Management of disease progression that occurs during imatinib therapy may include increasing the imatinib dosage; the use of an alternative TK inhibitor (dasatinib [Sprycel; BMS] or nilotinib [Tasigna; Novartis]); hematopoietic stem cell transplantation (HSCT), or enrollment in a clinical trial. Traditional chemotherapy regimens may also be considered for blast crisis.
The NCCN guidelines conclude, "The development of imatinib...has revolutionized the treatment of CML." Before the advent of imatinib, CML was treated medically with interferon alpha and low-dose cytarabine. According to ABC, Abdul-Jabbar is a spokesperson for Novartis, the manufacturer of imatinib.
The FDA approved imatinib for the first-line treatment of CML in December 2002.
NCCN = National Comprehensive Cancer Network.
Image of Abdul-Jabbar in 2007 from Flickr.
And another thing that Avastin (bevacizumab; Genentech) may be good for:
The anti-VEGF monoclonal antibody improved hearing loss and reduced tumor volume in patients with growing vestibular schwannomas. The conclusions are based on data from a small, first-of-its-kind study of patients with neurofibromatosis (NF) type 2—data which are available in an early release article from The NEJM.
Ten consecutive patients with NF type 2 and progressive vestibular schwannomas (who were not candidates for or declined the standard treatment of surgery and radiation therapy*) received at least one dose of bevacizumab (5 mg/kg every 2 weeks). The median annual growth rate of schwannomas before treatment was 62%, and the median duration of treatment was 12 months. (The rationale for assessing bevacizumab in NF-associated schwannomas is based on the expression of VEGF in tumor cells. However, the expression of the VEGF receptor, VEGFR-2, on tumor vessels is not particularly high—which suggests that an anti-VEGF-receptor drug is less likely to be of benefit than bevacizumab.)
In a retrospective analysis, 9/10 tumors shrank (best median response, 26% reduction) after bevacizumab treatment, and 6 demonstrated an imaging response. Only 1 patient experienced an increase in tumor volume (of 32%). Tumor reduction strongly correlated with baseline vasogenic edema on MR images (ie, the mean apparent diffusion coefficent). Improvements in hearing (at <12 weeks) were observed in 5 of 7 eligible patients and were progressive and durable (up to 16 months) in most.
This pilot study was not funded by Genentech; although 1 author (Gregory Sorensen, MD) reported receiving grant support from the company.
NF2 is a dominantly inherited disorder with a prevalence of 1 in 25,000. The most common tumor type associated with the condition is vestibular (or acoustic) schwannomas, benign tumors of the 8th cranial nerve. Growth of tumors causes progressive hearing loss, as does surgical and radiation therapy. Progressive vestibular schwannomas can also produce brainstem compression.
In May, the FDA approved Avastin for the treatment of the uniformly fatal brain tumor, glioblastoma multiforme, after standard therapy.
VEGF = vascular endothelial-cell growth factor.
* Eight patients were at high risk for complete hearing loss with standard therapy.
Delivering chemotherapy to brain tumors is particularly challenging because of the blood-brain barrier (BBB), the collection of tight junctions between endothelial cells in cerebral blood vessels. When intact, these protective junctions prevent the passage of a number of substances—including chemotherapeutic molecules—from the systemic circulation into the brain tumor bed. The key to effective, targeted therapy of brain tumors is to 1) selectively disrupt the BBB to allow the entry of cancer-killing drugs and then 2) reestablish the BBB so that chemotherapeutic agents are retained within the tumor bed.
Biomed engineers at Duke have constructed a prototype of an intravascular catheter, which can deliver BBB-busting hyperthermia* and provide real-time 3D imaging of brain tumors. The thin, flexible catheter is intended to be snaked through the internal jugular vein (which obviates the need for invasive cranial surgery) and manipulated into the dural venous sinuses. The investigators' proof-of-concept experiments, performed in dogs, was published in this month's issue of Ultrasonic Imaging.
The investigators concluded that their next-generation device must be smaller and more flexible than the prototype, to negotiate the curves of the cerebral vasculature. The long-term plan for the catheter is to obtain fluoroscopic-guided access to brain tumors through the venous sinuses, administer BBB-disrupting heat, which would then trigger the release of chemotherapeutic agents to the tumor bed.
* A temperature rise of approximately 5 degrees C.
Depiction of dural sinus system from Gray's Anatomy.
