Online First/Online Only
Articles/items published ahead of print or only online.
Friday, February 27, 2015
BY ROBERT H. CARLSON
Eight weeks versus 28 weeks of androgen suppression before radiotherapy produced virtually identical outcomes at 10 years of follow-up in men with intermediate-risk prostate cancer, in the randomized Phase III Radiation Therapy Oncology Group (RTOG) 9910 trial, published in the February 1st issue of the Journal of Clinical Oncology (2015;4:332-339).
The rates of 10-year disease-specific survival, overall survival, cumulative incidence of locoregional progression, distant metastasis cumulative incidence, and antigen-based recurrence cumulative incidence were all equal or within one or two percentage points between the two groups.
But an important question not asked or answered in the trial was whether some men with intermediate-risk prostate cancer can safely avoid androgen suppression entirely prior to radiotherapy. Also, the significance of the trial outcome may be less certain because the dose of radiotherapy used was less than is commonly used today.
RTOG 9910, sponsored by the National Cancer Institute, included 1,489 men with intermediate-risk prostate cancer randomly assigned to either a short-duration androgen-suppression regimen lasting eight weeks, or a prolonged-suppression regimen of 28 weeks. Patients in both groups were then treated with radiotherapy and an additional eight weeks of androgen suppression.
Those in the short-duration group therefore received a total of 16 weeks of androgen suppression, versus 36 weeks in the prolonged-duration group.
In a telephone interview, the first author, Thomas M. Pisansky, MD, Professor of Radiation Oncology at the Mayo Clinic, said that a lower than expected prostate cancer death rate reduced the ability of the results to detect a between-group difference in disease-specific survival. Nevertheless, he and his coauthors concluded that the schedule of eight weeks of androgen suppression before radiotherapy plus eight weeks of androgen suppression during radiotherapy remains a standard of care in men with intermediate-risk prostate cancer.
Accompanying Editorial by Anthony D’Amico
In an accompanying editorial (JCO 2015;4:301-303), Anthony V. D'Amico, MD, PhD, Professor of Radiation Oncology at Harvard Medical School and Chief of the Department of Genitourinary Radiation Oncology at Brigham and Women's Hospital and Dana-Farber Cancer Institute, questioned whether the trial had the power to show benefit from a longer duration of radiotherapy.
Those concerns were based on the inclusion of men in the trial who had intermediate-risk disease but a favorable prognosis and who may not have needed androgen suppression at all, which he D’Amico said diluted the power of the study to measure difference in outcomes.
Intermediate-risk prostate cancer was defined for the purposes of the trial by three sets of specifications: T1b-4, Gleason score 2 to 6, and prostate-specific antigen (PSA) between 10 and 100 ng/mL; or T1b-4, Gleason score 7, and PSA less than 20 ng/mL; or T1b-1c, Gleason score 8 to 10, and PSA less than 20 ng/mL.
Prior androgen-suppression therapy was not allowed unless a luteinizing hormone-releasing hormone analog (LHRHa) was started within 30 days before random assignment and bicalutamide or flutamide was started within 14 days of the LHRHa. Any finasteride was discontinued.
The radiotherapy used was two-dimensional or three-dimensional conformal external technique, but intensity modulation and brachytherapy were not allowed.
The prostate and any extraprostatic tumor extensions received 70.2 Gy in 39 daily fractions. The iliac lymph nodes received 46.8 Gy in 26 fractions, when included.
The median age of the men was 71 years for both groups, ranging from the mid-40s to the mid-80s.
The authors said that prior studies in these men showed that radiotherapy with androgen suppression reduced the risk of death from prostate cancer compared with use of radiotherapy alone.
Results Virtually Identical
For the 752 patients in the short-course androgen-suppression arm and the 747 in the prolonged androgen-suppression arm, a median duration of 9.4 years follow-up showed that the:
· 10-year disease-specific survival rate for the eight-week group was 95 percent, compared with 96 percent for the 28-week group;
· 10-year overall survival rates were 66 percent and 67 percent respectively;
· 10-year cumulative incidences of locoregional progression were six and 4 percent, respectively;
· 10-year distant metastasis cumulative incidences were both six percent; and
· 10-year prostate-specific antigen- based recurrence cumulative incidences were both 27 percent.
In the patients receiving short-term androgen suppression, there were 230 deaths, 29 as a result of prostate cancer and one due to complications of treatment. In the prolonged- treatment group, 220 patients died, 23 from prostate cancer and one from complications of treatment.
The authors acknowledged that the radiotherapy used was the standard more than a decade before the trial concluded and is no longer recommended, so the study may overestimate the incidence of biochemical failure, salvage therapy, and adverse events that might be expected with conformal radiation.
‘Not Convinced about Trial’s Conclusions’
D’Amico, though, said he was not convinced about the trial's conclusions: “Whether four months of androgen deprivation is sufficient, or if any androgen deprivation is necessary in men with unfavorable or favorable intermediate-risk prostate cancer, to minimize prostate cancer specific mortality, remains unanswered.”
He said that at this time, withholding androgen-deprivation therapy in men with favorable intermediate-risk prostate cancer, or adding four or six months of androgen deprivation to radiotherapy in men with unfavorable intermediate-risk prostate cancer, are both reasonable options based on the available evidence.
The definition of an intermediate-risk favorable subgroup that he cited, from Memorial Sloan Kettering, is a patient with Gleason 3 + 4 or less and a positive prostate biopsy not exceeding 50 percent and only one intermediate-risk factor excluding 4 + 3.
The intermediate-risk unfavorable subgroup would be patients with Gleason 4 + 3 or at least two intermediate-risk factors or at least one intermediate risk factor and a positive prostate biopsy greater than 50 percent.
“The clinical significance of this subdivision relates to personalizing the use of androgen-deprivation therapy for men with intermediate-risk prostate cancer,” D'Amico said.
In an e-mail exchange, he said that if a significant number of men in the study were in the favorable intermediate-risk group, which is likely based on the very low death rate at 10 years from prostate cancer, then the study loses power (or the ability) to measure a difference in death from prostate cancer between the two randomized treatment arms: “This is true because for men with favorable intermediate-risk prostate cancer, several studies have shown no significant association with a decrease in death from prostate cancer when
varying durations of hormonal therapy were added to radiotherapy.
“The most important point is that when you run a trial where the question is whether a longer duration of hormonal therapy will decrease death from prostate cancer, and some men enrolled in the study do not benefit from any hormonal therapy--in this case the favorable intermediate-risk patients--then any benefit from the longer duration of hormonal therapy in men with more advanced (i.e., unfavorable intermediate-risk prostate cancer) gets diluted, and both arms can end up looking the same, whether it is the eight-week or the 28-week hormonal therapy arm.”
“That means this study, instead of having a total of a certain number of patients, really has that number minus the number of people in the subset who do not benefit from any hormonal therapy,” he said. “And that is why the power of the study to measure the difference is decreased.”
D'Amico said it is very possible that patients in the unfavorable intermediate-risk arm—“how many there are in this study we do not know”--may benefit from more hormonal therapy. “We already know that six months prolong survival, and we know that four months prolong survival.” But whether nine months is better than the four months in this study is yet to be told.
D'Amico said he is awaiting the post-randomization analyses of the RTOG 0815 and the GICOR 17 randomized control trials within the intermediate-risk subgroups, for the latest data.
Commentary's Criteria Not Validated
Pisansky responded to D'Amico's critique in a telephone interview: “Our study tested the duration of androgen suppression with radiotherapy, as well as it has been tested to date, and we did not find any benefit to extending its duration beyond four months. This is simply the most objective way of looking at this study and its findings.
“The only thing that occurred as a consequence of prolonged androgen suppression was more side effects.”
He noted that during the time the study was being prepared for publication, another study looking at short-term versus intermediate-term androgen suppression was published, and this too found no benefit to longer-term use of androgen suppression in intermediate-risk prostate cancer (Denham et al. Lancet Oncology 2014;10:1076–1089).
RTOG 9910 entered approximately 1,500 patients over four years and followed patients for nearly a decade thereafter, he said.
Pisansky said that although D’Amico as the editorial writer did not seem to agree totally with the study's conclusions, the critique appears to be based on information (Zumsteg et al. Eur Urol 2013;64:895-902) that became available well after RTOC 9910 was designed and completed.
Moreover, Pisansky said, that information has not been validated by others (Castle et al. Int J Radiat Oncol Biol Phys. 2013;85:693-699 and Rodrigues et al. Radiother Oncol 2013;109:204-210), nor adopted as a risk stratification scheme for intermediate-risk prostate cancer by any consensus group.
“There is certainly a range of prognoses within intermediate-risk prostate cancer, and there are those patients with more 'favorable' versus 'unfavorable' outcomes,” Pisansky continued. “However, focusing mainly on stratification based on Gleason grade 3 + 4 and the percentage of positive biopsy to separate 'favorable' from 'unfavorable' may be premature, as other studies that look at changing the risk stratification for intermediate-risk prostate cancer did not show that the percent of positive biopsy was an important ingredient.”
But RTOG 9910 did provide information on patients with “unfavorable” intermediate-risk disease, Pisansky said, based on the number of risk factors. In fact, the group with multiple intermediate-risk factors and those with what may be now considered high-risk disease made up more than half of the study's patients, and even there the researchers did not observe a benefit to androgen suppression beyond four months’ use.
“Even if one were to think that the study should have tested the more prolonged androgen suppression only in the more 'unfavorable' intermediate-risk patients, still, more than 7,000 patients would be needed--a monumental task and is simply not realistic,” he said.
RTOG 9910 did not address the question of whether omitting androgen suppression is a reasonable option for intermediate-risk patients, Pisansky said, but noted that a prior RTOG study (Jones et al. NEJM 2011;365:107-118) did show a benefit of four months for androgen suppression in intermediate-risk prostate cancer, as did another study using higher radiation doses.
“We mentioned in our paper that another study, RTOG 0815, is currently accruing patients specifically meant to address the issue that Dr. D'Amico brings up--namely whether certain patients with more favorable intermediate-risk benefit from androgen suppression at all, but results of that study are years off. For the here and now, I think RTOG 9910 is as good as any study can be to answer the question we asked.”
William Oh: Optimal Management of Intermediate-Risk Prostate Cancer Has Long Been Controversial
For a urological oncologist's point of view on RTOG 9910, William K. Oh, MD, Chief of the Division of Hematology and Medical Oncology and Professor of Medicine and Urology at Mount Sinai School of Medicine, was asked for his perspective.
He said the optimal management of intermediate-risk prostate cancer has been controversial for some time because randomized trials have suggested that both increased doses of radiation and concurrent use of androgen-deprivation therapy can have benefit in terms of clinical outcomes.
The report on RTOG 9910 by Pisansky and colleagues suggests that nine months of ADT appears to have no significant advantage over four months of androgen deprivation therapy in intermediate-risk patients treated with 70.2 Gy of external beam radiation, Oh said.
This was a large study and well conducted, he said, but the standard of care for radiotherapy in intermediate-risk prostate cancer has evolved over the years since that trial began, to include both higher standard doses of radiation as well as better risk stratification of intermediate-risk disease to favorable and unfavorable categories.
“What we can generally say with 9910 is that nine months of androgen deprivation therapy in general will not benefit intermediate-risk patients. But it does not tell us if androgen deprivation therapy is not needed for some lower-risk intermediate patients.”
For that question, he said, RTOG 0815 is asking whether a higher dose of radiation and no androgen-deprivation therapy versus six months of androgen deprivation therapy is of value.
'Take-Home Message Clear, But Not News'
A radiation oncologist asked to comment, Sabin B. Motwani, MD, Assistant Professor in the Department of Radiation Oncology at Robert Wood Johnson Medical School, Cancer Institute of New Jersey, said RTOG 9910 asked a good question at the time it was initiated.
He noted that the standard of eight weeks neoadjuvant androgen suppression and eight weeks concurrently with radiotherapy had been set previously by RTOG 8610, but this was for locally advanced prostate cancer in the pre-PSA era. Animal data had suggested that extended androgen suppression before radiotherapy was effective and that led to conducting this trial.
“But more than a decade since the initiation of RTOG 9910, we already know that for intermediate-risk prostate cancer there is a survival benefit with androgen suppression from the D'Amico trial and RTOG 9408. Both trials used eight weeks of neoadjuvant androgen suppression before radiotherapy,” Motwani said. “The total duration of androgen suppression in those trials was six months and four months, respectively. Now the question for intermediate-risk prostate cancer is not necessarily how long the hormone suppression should be given but rather whether it should be given at all, given all the adverse effects of hormonal therapy.”
Motwani also noted that RTOG 9910 used 70 Gy, but in 2015 most radiation oncologists treat to much higher doses, in the range of 78-80 Gy.
“RTOG 0815 will provide valuable information in the setting of modern radiation doses, whether six months of androgen suppression is necessary or not in the intermediate-risk prostate cancer population.” he said.
Thursday, February 26, 2015
BY ROBERT H. CARLSON
Final analysis of the large randomized Phase III placebo-controlled COU-AA-302 prostate cancer trial, published in the February issue of Lancet Oncology (2015; 2:152-160) show that use of abiraterone with prednisone increased overall survival compared with prednisone-placebo--34.7 months versus 30.3 months--in patients with castration-resistant, metastatic disease who had not previously received chemotherapy. Use of abiraterone also prolonged the median time to opiate use for prostate cancer-related pain: 33.4 months vs. 23.4 months.
These results follow the study’s interim report in 2013 (Ryan et al: NEJM 2013;368:138-148) showing that median time to progression had approximately doubled with abiraterone-prednisone (16.5 vs. 8.3 months).
Median overall survival had not been reached at the time of the interim report, noted Charles J. Ryan MD, Professor of Clinical Medicine and Urology and the Thomas Perkins Distinguished Professor in Cancer Research, and Program Leader of Genitourinary Medical Oncology at UCSF Helen Diller Family Comprehensive Cancer Center.
“The survival data took a few years to fully mature, and although the survival curves separated earlier in the course of the trial, it took further maturation for the statistically significant survival separation to emerge.”
Should abiraterone now be considered a standard of care? “Absolutely,” Ryan said. “Prior to this study there was no standard of care for patients with castration-resistant prostate cancer who are asymptomatic. And there was also no standard of care for patients for whom chemotherapy was not an option. This is important because in castration-resistant prostate cancer, previous data had suggested that only about 45 percent of patients were ever receiving chemotherapy. So there was a large unmet need for a therapy that could prolong survival and delay progression of the disease with non-cytotoxic approaches.”
Rationale for Combining with Prednisone
Prednisone was combined with abiraterone in this trial, and also in the control arm, because it has shown benefits in prostate cancer, he continued. “Prednisone has long been associated with palliative care in this disease, and 25 to 30 percent of patients experience a clinical response to prednisone. That's why the curves of the two arms failed to separate immediately in this trial and why there was some prolongation in the time until the full benefits of abiraterone in the treatment arm were seen, because of the modest effect of prednisone in the controls.”
A total of 44 percent of patients in the placebo arm went on to receive abiraterone. Ryan said that rather than confounding the results, crossover from placebo to abiraterone only strengthened the results.
“If the trial had been negative, we would have said the crossover confounded the data. But the fact that the crossover occurred and the trial was still positive for both primary endpoints strengthens the interpretation of the data.”
In 2011, the Food and Drug Administration approved abiraterone for use in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer who have received prior chemotherapy containing docetaxel. In 2012, the FDA approved an expanded indication for abiraterone in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer before chemotherapy.
In the COU-AA-302 trial, which was funded by Janssen Research & Development, a total of 1,088 asymptomatic or mildly symptomatic patients with chemotherapy-naive prostate cancer stratified by Eastern Cooperative Oncology performance status (0 versus 1) were randomly assigned to receive either abiraterone (1,000 mg once daily) plus prednisone (5 mg twice daily) or placebo plus prednisone.
At a median follow-up of 49.2 months, the median overall survival time was significantly longer in the abiraterone group than in the placebo group, 34.7 vs. 30.3 months; and the mortality rate was also reduced--65 percent (354 of 546 patients) versus 71 percent (387 of 542 patients), respectively.
Similarly shortened, the median time to opiate use for prostate cancer-related pain was 33.4 months in the abiraterone acetate group versus 23.4 months in the placebo group.
The most common grade 3/4 adverse events reported were cardiac disorders--in eight percent of the abiraterone group versus four percent in the placebo group; increased alanine aminotransferase--six percent versus less than one percent, respectively; and hypertension--five percent versus three percent.
Inhibits CYP17, Secondary Androgen Biosynthesis
In a commentary accompanying the COU-AA-302 trial report (Lancet Oncology. 2015; 2:119-121), Ravi A. Madan, MD, Clinical Director of the National Cancer Institute’s Genitourinary Malignancies Branch, and William L. Dahut, MD, Clinical Director of the NCI’s Center for Cancer Research, write that the trial reaffirms the importance of secondary androgen biosynthesis inhibition in patients with metastatic castration-resistant prostate cancer.
Elaborating in a telephone interview, Madan explained that abiraterone targets the CYP17 pathway, blocking the biosynthesis of androgens in the tumor microenvironment, in contrast to the situation with commonly used anti-androgens, which manipulate the endocrine system to block testicular production of testosterone.
“It's sinister that a cancer cell can produce its own fuel,” Madan said.
He added that abiraterone is one of several new drugs for metastatic castration-resistant prostate cancer, including enzalutamide, sipuleucel, cabazitaxel, a modified version of docetaxel, and the radiopharmaceutical radium-223 dichloride. There is no clear data on combinations or sequencing of these drugs, and Madan said clinicians have to weigh the side effects and potential benefit.
“With enzalutamide, for example, there is concern that patients with a history of seizures or risk of seizures may have increased seizure risk, so for that patient the clinician might consider abiraterone. On the other hand, abiraterone contains steroids which might be problematic for patients who have diabetes and so providers may choose to use enzalutamide. In addition, the enzymatic blockade with abiraterone could lead to endocrine consequences, such as fluid retention and high blood pressure.”
Emerging data suggest that by using enzalutamide and abiraterone sequentially, the benefits from the second seem to be diminished relative to the first, possibly due to development common mechanisms of resistance, Madan said.
Clinical trials are underway to discover optimum sequencing and combinations, and a trial combining radium 223-dichloride with abiraterone is now recruiting patients (NCT02043678). In addition, Madan is involved in a trial combining enzalutamide with a therapeutic vaccine (NCT01867333).
In the commentary about the COU-AA-302 study, Madan and Dahut called the responses remarkable—and, because patients randomly assigned to placebo plus prednisone were ultimately treated with abiraterone, the report most likely underestimated the survival advantage to abiraterone.
Thursday, February 26, 2015
By Robert H. Carlson
Cancer patients who use palliative care services are 50 percent less likely to use the emergency department (ED) during the last month of life compared with cancer patients not receiving palliative care, according to new research.
It has been well known that emergency departments are overused by many patients toward the end of life. Identifying risk factors associated with ED may help develop strategies to reduce that use, said the study researchers, all from the Cicely Saunders Institute of Palliative Care, Policy & Rehabilitation at King's College London, U.K.
In the meta-analysis published in the February 1 issue of the Journal of Clinical Oncology (2015;4:370-376), the researchers identified the following risk factors for increased use of EDs in the last month of life:
· Male gender (odds ratio 1.24);
· Black race (odds ratio 1.45 compared with white race);
· Lung cancer (odds ratio 1.17, with reference to other cancers); and
· Lowest socioeconomic group (odds ratio 1.15, with reference to highest socioeconomic status).
Cancer patients receiving palliative care were less likely to attend the ED in their last month of life (odds ratio 0.50), versus those not receiving palliative care.
“Palliative care services remain underused for cancer patients, and this finding supports increased referrals of cancer patients to palliative care or supportive care services,” the first author, Lesley Henson, MD, a Clinical Training Fellow at Cicely Saunders and a palliative care physician, said via email.
30 Studies Combining Data from 1.8 Million Patients
The meta-analysis identified 30 studies combining data from 1,181,842 patients. The majority were in the U.S. (18 studies) and Canada (eight studies), with the rest from the Republic of Korea, Spain, and Taiwan. The study used the reporting outcome of more than one ED visit in the patient’s last 30 days of life.
“Our finding has added further high-quality evidence to the scientific literature demonstrating the benefits that can be gained from palliative care,” the authors wrote. “Since current financial health care constraints have necessitated policy and services to evolve immediately, especially those that can reduce ED attendance... these findings may be used to develop screening interventions for high-risk cancer patients and also provide evidence to assist policy-makers to direct resources.”
Henson said there is no evidence that overly aggressive care at the end of life (defined as more than one ED visit) improves life expectancy, and in fact, such care is associated with a reduced quality of life for patients and their families. “Yet, despite the potential negative impact to individuals and society, multiple ED visits by cancer patients in their least 30 days of life has increased over time.”
The limitations of the meta-analysis, she said, include the heterogeneity of the review studied, estimates that combined univariable and multivariable effects, and the fact that although the factors identified provide important information on association, causality cannot be inferred.
Also, there was a lack of studies investigating patients’ and/or caregivers’ preferences for health care services. For example, he said, patients may prefer for someone to come to their home, to be admitted directly to the oncology ward, or to have a 911 call (999 in the U.K.).
Still, the researchers acknowledged that at times, the ED is actually the most appropriate setting: “The importance of providing individualized patient-centered care, including ED care if required, must not be overlooked.
Future studies, Henson said, may investigate psychosocial factors and patients’ and caregivers’ preferences for emergency care services.
Eduardo Bruera: ‘Simple and Easily Measurable Factors’
Asked for his perspective for this article, Eduardo Bruera, MD, Chair and Professor of the Department of Palliative Care and Rehabilitation Medicine at the University of Texas MD Anderson Cancer Center, said the study provides valuable information because the authors found simple and easily measurable factors associated with ED visits, and confirmed that palliative care referrals are associated with reduced ED visits.
“ED visits in the last days of life are distressing for patients and families, and reducing them is an important goal for cancer programs,” he said via email. “Oncology programs can take advantage of these findings and institute early (outpatient) referral to palliative care as a way to prevent ED visits.”
The study itself is of high quality, with an important systematic review of the existing literature, Bruera said.
“The limited number and small size of outpatient supportive care/palliative care programs in the U.S. is one of the main barriers to implementing checklists for identification of patients at risk and ensuring early palliative care access for them.”
He added that more and larger outpatient palliative care programs will allow for large cooperative studies on the prevention of ED visits.
Tuesday, February 24, 2015
BY SARAH DIGIULIO
In a much-talked-about study in Science (2015;347:78-81), Cristian Tomasetti, PhD, and Bert Vogelstein, MD, quantified (for the first time) a strong positive correlation between the variation in cancer risk among different organs and the number of stem cell divisions in those organs. Although many of the resulting headlines and think pieces in the lay press overemphasized—and in many cases misinterpreted—the link between “cancer risk” and “luck,” cancer biostatisticians say the paper is a significant step in understanding the biology of what drives cancers to arise and highlights key directions for future research.
BERT VOGELSTEIN, MD
CRISTIAN TOMASETTI, PHD
Asked for his opinion for this article, Giovanni Parmigiani, PhD, Professor and Chair of the Department of Biostatistics and Computational Biology at Dana-Farber Cancer Institute, said the point of the paper is essentially a very simple one: to show the correlation between the number of stem cell divisions in a tissue and the likelihood of a cancer arising in that tissue. “It’s not necessarily a causal relation, but it is a very very important correlation to be aware of. And it is the first time this correlation has been quantified.”
Although he was not involved in this latest work, Parmigiani has worked with both Vogelstein and Tomasetti in the past on earlier genome cancer projects in Vogelstein’s lab, as well as other biology mathematical modeling projects.
“The paper represents a genuine breakthrough in our understanding of how cancer arises,” Parmigiani said in a phone interview. “It is the first time that anyone can quantify the effect of the imprecise fidelity of cell division in the oncogenetic process. … Nobody before had collected so systematically and accurately the number of cell divisions that tissue-specific stem cells undergo during the course of one’s lifetime.”
The paper set out to determine—as Vogelstein, Professor of Oncology and Pathology and Director of the Ludwig Center for Cancer & Therapeutics at Johns Hopkins Kimmel Cancer Center and Howard Hughes Medical Institute Investigator; and Tomasetti, Assistant Professor in the Division of Biostatistics and Bioinformatics in the Department of Oncology at Johns Hopkins Kimmel Cancer Center, note in the opening paragraphs—given that hereditary and environmental factors cannot fully explain the differences in organ-specific cancer risk, how else the differences in cancer risk between tumor types could be explained.
Also speaking via telephone, Vogelstein said that before the paper was published there was undoubtedly an understanding that “replicative mutations—a stochastic component or ‘bad luck’”—were involved in cancer development. “That’s unquestionable. But this was the first time that this component could actually be measured.”
The findings suggest, he explained, that for the 31 cancer types included in the data, two-thirds of the mutations that are required for cancer appear to be explained by replicative factors that occur simply because cells are dividing.
Based on previous research (including genome-wide analyses) finding that genetic and epigenetic changes in large part drive the development of cancer, the authors theorized that the stochastic effect associated with the lifetime number of stem cell divisions within each tissue are a major contributor to cancer overall and can be more important than hereditary or external environmental factors. The more frequently stem cells in a certain tissue divide, the more likely a cancer is going to develop in that tissue.
As Tomasetti and Vogelstein explained in the paper, they plotted the total number of stem cell divisions during the average lifetime of a human against the lifetime risk for cancer of the tissue type of that tumor. A total of 31 tissue types in which stem cells had been quantitatively assessed were used for the analysis, along with the lifetime cancer incidence risk in the U.S. for those cancer types based on data from the Surveillance, Epidemiology, and End Results database.
The data showed a highly positive correlation—with a linear correlation coefficient of 0.804, suggesting that 65 percent of the differences in cancer risk (between 39 and 81 percent based on the 95 percent confidence interval) among different tissues can be explained by the number of stem cell divisions in those tissues. And, as noted in the paper, that finding suggests that the stochastic effect of DNA replication appears to be the major contributor to cancer in humans.
The authors offer further evidence of their theory by assigning each cancer type in the study an “extra risk score”—defined (for the purpose of the paper) as the product of lifetime risk and the total number of stem cell divisions. A high extra risk score (high cancer risk for a particular tissue relative to the number of stem cell divisions in that tissue) therefore would indicate that environmental or inherited factors should play a relatively more significant role in that cancer’s risk. And the data showed that the tumors with relatively high extra risk scores (including familial adenomatous polyposis and Lynch syndrome colorectal cancers, basal cell carcinoma, and lung cancers in smokers) were those with known links to specific environmental or hereditary risk factors.
A key point of the paper was defining replicative mutations as mutations that are caused solely by the process of normal DNA replication, Vogelstein said. “Every time a perfectly normal human cell divides—even in a test tube—it will make about three mutations. That’s been measured. It’s a side effect of evolution—cells make mistakes.”
Such random replicative mutations are not the only mutations that cause cancer, though, of course; the others are inherited genetic mutations or environmental-associated mutations caused by exposure to carcinogens such as cigarette smoke or sunlight.
It has been suggested that other stochastic components (i.e. other forms of “bad luck”) also play a role in cancer, he added. “For example, the immune system and epigenetic switches may also play a role. But our research shows that the majority of the stochastic component can be attributed to mistakes made during DNA replication.
“The theory explains why many cancers may not be preventable by changing lifestyle or environment,” Vogelstein said.
View from a Cancer Stem Cell Expert
Commenting for this article in a phone interview, cancer stem cell biologist Quintin Pan, PhD, Associate Professor and Research Director of the Head and Neck Oncology Program at The Ohio State University, agreed that the key takeaways from the paper have big implications for his field. The findings support the theory that normal stem cells are the cells of origin for cancer, he said.
“The cell origin for cancer has been a mystery—and it is still a mystery,” he explained. The stem cell hypothesis posits that a unique cell population, cancer stem cells are the only cells that can initiate and repopulate a tumor. And, Pan added, the Vogelstein paper suggests the intriguing idea that normal stems cells through accumulated mutations may be the cell of origin for cancer stem cells—providing the first evidence to support the suggestion that normal stem cells can be reprogrammed into cancer stem cells through mutations.
“The data presented in this paper suggest that mutations in normal stem cells may convert those stem cells into cancer stem cells. … I think the advance [from this paper] is that perhaps it’s the mutations in the normal stem cell compartment that can lead to/subsequent replication of these mutated stem cells leading to an increase in cancer risk.”
The next step for the research is to further validate the findings and then reveal the driver mutations in the normal stem cells that promote oncogenesis, Pan added. “As a cancer biologist with a focus on anti-cancer therapeutics, I am interested to know: What are the key mutations? And which mutations are indispensable to promote cancer? These key pieces of puzzle are needed so we can begin to design therapies that can target these critical genetic abnormalities and hopefully cure cancer.”
Key Implications for Cancer Biologists
Right now, the key implications are for cancer biologists, Parmigiani said: “Don’t take for granted that if we work at it hard enough we will be able to pin down cancer-wide genetic theories or environmental and behavioral factors [that cause cancer]. There could potentially be a hard core of randomness that we will never be able to get rid of.”
GIOVANNI PARMIGIANI, PHD
Parmigiani said the findings do affect his work in cancer biostatistics and computational biology: “In terms of understanding mechanisms of variability and mechanisms of cancer progression, the paper opens up many new avenues for thinking about cancer evolution, especially from a mathematical standpoint. And it gives us a key through which we can try to interpret the effect of genetic variation or environmental exposures that are known to cause cancer. We can now try to see whether cancers are developing based on this channel of the number of stem cell divisions—or they are acting independently. In a search for understanding the mechanism of cancer, I think this is a very important guiding light.”
But, he added: “This research is about understanding the biology [of cancer]. There’s a lot of work that we can do before we can go back to the community of oncologists and say, this is what this really means.
“Down the line I hope this will reinvigorate the efforts that we make for early detection,” he added
Implications for Prevention
In a “News & Views” article published in Nature last month in response to the paper, Dominik Wodarz, PhD, Associate Professor of Ecology and Evolutionary Biology in the School of Biological Sciences at the University of California, Irvine, and Ann Zauber, PhD, a biostatistician in the Department of Epidemiology and Biostatistics at Memorial Sloan Kettering Cancer Center, note that a key takeaway from the research is recognizing the significance of chemoprevention to slow the evolutionary processes of cancer development, as well as the generation of early-detection techniques (Nature 2015;517:563-564).
“The Tomasetti and Vogelstein paper highlights the importance of evolutionary mechanisms for the development of cancer; and further suggests that interfering with the evolutionary processes at work using specific drugs could prevent or delay cancer—chemoprevention,” Wodarz added in an email.
The challenge is that screening is currently difficult for many cancers, especially rare cancers, Wodarz and Zauber noted in their article. To be effective, screening needs to be used in settings where the benefits achieved outweigh the risks of complications from the screening and also outweigh the burden of false positives that cause excess testing and worry.
“If random genetic changes are more relevant drivers of carcinogenesis, then biomarkers and early detection methods will have to be developed to prevent cancer mortality in the general population.”
Another important takeaway from the Tomasetti and Vogelstein paper is to be aware of the degree of chance in cancer development in terms of recognizing who is at risk for various types of cancer, Zauber added via email. “We need to allow for imperfection in identifying all who are at risk for a given cancer. We use information of who is at higher risk and needs further surveillance—but we cannot forget that many (or most) of the rest of cancer cases are probably arising in those without immediately identifiable risk factors. We must be aware of this large random component to cancer development and be ready to follow up with a wider group of at-risk individuals who might be at risk.
“The challenge is how to accomplish a larger surveillance without causing harms from un-needed testing.”
ANN ZAUBER, PHD
Monday, February 23, 2015
BY MARY BROPHY MARCUS
The Center to Advance Palliative Care (CAPC) is now a membership organization, changing as of January from one that had been supported mainly by donations. Rather than individuals, though, the members are institutions and organizations--hospitals, nursing homes, home care agencies, office practices, associations, and other groups in the medical community seeking the type of information and training tools for palliative care that CAPC provides.
"There are stronger and stronger incentives for delivery of high-quality care for the sickest, most complex, and costliest patients, and the model of care that has been repeatedly shown to improve quality and in so doing, reduce reliance on 911 calls, ED visits, and hospitalization is palliative care," CAPC Director Diane E. Meier, MD, said in an interview. Multiple studies support the use of palliative care to improve the quality of life of patients as well as family members.
She explained that when CAPC first opened its doors in 1999 as part of Mount Sinai Medical Center, the goal was to strengthen access to hospital palliative care.
At the onset, she noted, CAPC was funded completely by Robert Wood Johnson Foundation, a situation that continued until 2006 when additional funders came forward. And although the foundation ceased their funding in 2011, CAPC was able to continue with the support of many other foundations, as well as some individual donors.
Moving Beyond Hospitals
"About two years ago, it became clear that our original mission to strengthen access to hospital palliative care was essentially completed,” Meier said. “Ninety percent of larger hospitals now report a palliative care service, and that is rapidly becoming the standard of practice in hospitals.”
But, she said, there is a clear need for palliative care expertise everywhere, not just in hospitals: "Hospitals have a strong incentive to invest in palliative care, but that wasn’t the case for nursing homes, home care agencies, assisted living facilities, or primary care offices until the passage of the Affordable Care Act.”
Now with the passage of the ACA, there is a business case for the delivery of palliative care across the continuum: "We need to widen our focus beyond hospitals to all settings to where seriously ill people need help. The vast majority of very sick patients are in their homes and communities and spend relatively little time in hospitals. In addition to the need to deliver palliative care beyond hospitals, there are nowhere near enough palliative care specialists to meet the needs of the U.S. population.
Thus, Meier said, CAPC is focused on two main priorities: (1) improving access to palliative care in all settings; and (2) strengthening the skills of every clinician who cares for seriously and chronically ill people. “Palliative care is needed long before people are dying,” she emphasized.
“Right now, most people with serious chronic illnesses are continuing to benefit from disease treatment, may live for years with their disease, and are therefore not eligible for hospice. These are the patients most in need of access to palliative care at the same time as their disease treatments.
"There's so much preventable suffering," Meier continued, adding that to ensure that there will be a workforce prepared to relieve that suffering--clinicians who treat people who will be coping with serious chronic illness for years and decades--palliative care training of oncologists, family practitioners, nurse managers, home care nurses, and nurses in nursing homes needs to increase.
CAPC Remains Not-for-Profit
Meier said it was actually another organization, Nurses Improving Care for Healthsystem Elders (nicheprogram.org), a nurse-driven program designed to help hospitals improve the care of older adults, that was the inspiration for the idea to transition to being member-based. "In a field that has been around for 10 to 15 years, there is now an audience with a capability to support us." Ten years ago, CAPC could not have succeeded as a member organization, she said, since there were very few programs, but now with the recent rapid growth and demand for palliative care services and the wide recognition and respect of palliative care as a specialty, the change was feasible.
So, how does the transition from a nonprofit donor-supported organization to one that has memberships come into play? Meier said that she and her colleagues recognized that to achieve these ambitious goals—training hundreds of thousands of clinicians in palliative care and ensuring access to palliative care in community settings--required going beyond a dependence on philanthropy. While CAPC is still not-for-profit, it needed to expand the financial resources.
Under the new structure, a single organization will pay one membership fee and gain access to training and support for the entire staff. At members’ fingertips will be a broad scope of support and educational options: Virtual office hours, webinars, operational and clinical training, and opportunities to share and collaborate with other palliative care experts. CAPC also offers members information on how to create a good measurement and monitoring system.
"I’d like to reach hundreds of thousands of physicians with core clinical training that they didn't get in medical and nursing school—and still aren't getting consistently," Meier said.
CAPC already has hundreds of organizational members—including about $1.8 million in membership commitments--meaning that there is a potential to reach tens of thousands of individual clinicians, she noted.
Information about membership can be found at https://www.capc.org/membership.
CAPC's director also said she would like to see access to quality palliative care become an accreditation requirement for health care organizations that serve Medicare, Medicaid, and privately insured individuals.
"Palliative care prolongs life. It improves quality of life and quality of care for our nation’s most seriously ill patients and their families. It’s appalling to me that it's not a required aspect of health care delivery right now," she said. "Access to palliative care that meets quality standards should exist wherever patients are in need--that's what I'm working for."
Evolving Definition of Palliative
Asked for her perspective for this article, Anne Coscarelli, PhD, Director of the Simms/Mann--UCLA Center for Integrative Oncology and Adjunct Professor of Medicine in the Division of Hematology/Oncology at the David Geffen School of Medicine, agreed that the definition of palliative care has evolved and is now being applied to survivorship: "We used to think that palliative care was a step to what became end-of-life, but now we're seeing that palliative care progresses through a continuum that begins with diagnosis and can lead into survivorship."