New results from the NCI-sponsored Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial show that screening for ovarian cancer with transvaginal ultrasound (TVU) and the CA-125 blood test did not result in fewer deaths from the disease compared with usual care. In addition, false-positive results from the two screening methods often led to unnecessary surgeries and other serious complications. The results were presented June 4 at the American Society of Clinical Oncology (ASCO) annual meeting and appeared online June 8 in JAMA.
The PLCO trial is a randomized, controlled trial of adults 55 to 74 years of age. The 78,216 women who enrolled were assigned to undergo either annual screening with TVU and CA-125 testing or to receive usual care. (Most women in the usual care group underwent bimanual examination with ovarian palpation.) Participants were screened at 10 centers across the United States between November 1993 and July 2001 and were followed for up to 13 years. There were 118 deaths from ovarian cancer in the screened group compared with 100 deaths in the usual-care cohort.
The false-positive rate in the PLCO trial was approximately 5 percent of those screened during each round of screening. Of the 3,285 women with false-positive results in the study, 1,080 underwent surgical follow-up. Among those, 163 women (15 percent) experienced at least one serious complication. A 2009 report on the PLCO study found that many of the positive screening results from TVU and CA-125 turned out not to be cancer. The researchers estimated that only 1.6 out of every 100 women who test positive for signs of ovarian cancer with these tests actually have cancer.
With these results, and the efficacy of these tests being ruled out, investigators will explore other screening options, the study authors noted. Some evidence suggests that ovarian tumors need to be found when they are relatively small—considerably smaller than the current threshold used for TVU, explained Dr. Christine Berg of NCI’s Division of Cancer Prevention. “Had the trial tested a lower CA-125 threshold, it may have been possible to detect cancers at an earlier stage,” said Dr. Berg. “However, this would be at the expense of more false-positive results and perhaps overdiagnosis of benign tumors.”
Prolonging treatment of patients with high-risk gastrointestinal stromal tumors (GIST) with the tyrosine kinase inhibitor imatinib (Gleevec) after surgery improved overall and recurrence-free survival in a prospective randomized multicenter trial. The trial results were presented June 5 at the ASCO annual meeting by lead author Dr. Heikki Joensuu of Helsinki University Central Hospital, Finland.
Researchers randomly assigned 400 patients with operable GIST who were at high risk for recurrence to either 1 or 3 years of adjuvant imatinib therapy. After a median follow-up of 54 months, the investigators found that 5-year recurrence-free survival was higher in the 3-year treatment group (65.6 percent) than in the 1-year treatment group (47.9 percent). Similarly, 5-year overall survival for patients in the 3-year treatment group (92.0 percent) was higher compared with that of patients who received adjuvant imatinib for only 1 year (81.7 percent).
“What really pleases me about this study is the impact on overall survival,” Dr. Joensuu said at an ASCO press briefing. Based on historical data before the introduction of imatinib treatment of high-risk GIST, “perhaps 50 percent of these patients would have died within the first 5 years, and now we are looking at 92 percent overall survival among the 3-year treatment group, which is very high,” he noted. In addition, there was a 55 percent reduction in the risk of death in the 3-year treatment group compared with the 1-year group, “a substantial reduction which is also statistically significant,” he said.
The researchers found that the longer imatinib regimen was generally well tolerated, and few of the patients developed resistance to the drug, which is in line with previous studies. Only 2 percent and 6.1 percent of patients in the 1- and 3-year groups, respectively, stopped treatment because the disease recurred.
“This might be the first example of long-term adjuvant therapy with a targeted small-molecule tyrosine kinase inhibitor, and it’s likely to become standard treatment,” said Dr. Joensuu in a press release.
Children’s Oncology Group researchers have shown in a phase III clinical trial that radically increasing the dose of methotrexate used to treat patients with high-risk B-cell acute lymphoblastic leukemia (B-cell ALL) significantly improves 5-year event-free survival (that is, survival without any serious health events) when compared with the current standard of care. The trial results were presented last week at the ASCO annual meeting.
In the current standard of care, known as the Capizzi regimen, patients are started on a low dose of methotrexate, and the dose is increased gradually over time. Methotrexate is then followed by treatment with a second chemotherapy drug called asparaginase. In the new approach, however, patients are given a dose of methotrexate that is about 50 times the starting dose in the Capizzi regimen, and asparaginase is not used.
The next generation of clinical trials involving patients with high-risk B-cell ALL will use the high-dose methotrexate regimen, said the trial’s lead investigator, Dr. Eric Larsen of Maine Medical Center. “Even for children not on a trial, it’s likely that this approach will be adopted.”
The Capizzi regimen has been very effective, improving cure rates for ALL by reducing relapses in the bone marrow, where the disease initially occurs. The investigators hypothesized that a high-dose regimen of methotrexate would more effectively target cancer cells in the central nervous system (CNS), where most B-cell ALL relapses occur.
The trial began in 2004 but was closed early in January 2011, Dr. Larsen explained, when a planned interim analysis showed that the high-dose methotrexate approach led to “clearly superior” 5-year event-free survival: 82 percent versus 75 percent. The high-dose methotrexate group also had significantly fewer bone-marrow and CNS tumor relapses.
Patients in the trial treated with the Capizzi regimen who were not more than a year into their treatment were given the choice of switching to the high-dose regimen, Dr. Larsen noted. Most, but not all, chose to switch.
“We were concerned that the high-dose methotrexate regimen would be more toxic, but it was found to be less toxic than the Capizzi regimen,” Dr. Larsen said.
The higher incidence of side effects in patients treated with the Capizzi regimen may be due to the asparaginase, Dr. Larsen suggested. Also, another chemotherapy drug, leucovorin, is typically used as a “rescue” therapy to help prevent common side effects associated with high doses of methotrexate (such as low blood cell counts, mouth sores, and diarrhea), which also likely helped explain the differences in toxicity of the two regimens, explained Dr. Lisa Diller of the Dana-Farber Cancer Institute and a Children’s Oncology Group investigator.
The high-dose methotrexate regimen should become the new standard of care in high-risk B-cell ALL, Dr. Diller agreed. Even with the gains in survival seen in pediatric cancer, she continued, the results are further evidence that with well-designed clinical trials “we can find new ways to improve outcomes with old drugs.”
Results from two phase III randomized clinical trials suggest that, at least for some patients with ovarian cancer, adding the antiangiogenesis agent bevacizumab to chemotherapy increases the time to disease progression and may improve survival. Longer follow-up is needed to confirm the trends, but, if upheld, the results of these trials would support the first use of a biologic agent to treat ovarian cancer. Data from both trials were presented last week at the ASCO annual meeting in Chicago.
In the OCEANS study, 484 women whose cancers recurred more than 6 months after a single prior regimen of chemotherapy were randomly assigned to receive chemotherapy with carboplatin and gemcitabine plus bevacizumab or a placebo. After six cycles of chemotherapy, the patients continued to receive bevacizumab or the placebo until evidence of tumor progression was seen. Those who received bevacizumab had a 52 percent increase in the time it took their disease to progress compared with those who received placebo (12.4 months versus 8.4 months, respectively).
Tumor shrinkage was observed in 79 percent of the patients treated with bevacizumab, compared with only 57 percent of those receiving the placebo. The duration of tumor response was also longer in patients receiving bevacizumab by an average of 3 months. Side effects were similar to those seen in other studies of bevacizumab, such as increased hypertension and proteinuria. No gastrointestinal perforations were reported.
“This regimen should be considered a new option for women with recurrent ovarian cancer [whose cancer responded to plantinum-based chemotherapy],” said the study’s lead investigator Dr. Carol Aghajanian of Memorial Sloan-Kettering Cancer Center.
In the second trial, known as ICON7, 1,528 women with newly diagnosed high-risk or advanced ovarian cancer were randomly assigned to six cycles of chemotherapy with carboplatin and paclitaxel alone or to six cycles of chemotherapy with bevacizumab, followed by bevacizumab alone for 12 cycles. The addition of bevacizumab modestly increased the time it took patients’ tumors to grow, from 17.4 months to 19.8 months. An interim analysis of overall survival showed fewer deaths among patients who received bevacizumab, but this difference was not statistically significant.
The subgroup of patients at the highest risk of recurrence—patients with stage IV disease or those with stage III disease who had more than 1 cm in diameter of remaining tumor after debulking surgery—had a statistically significant improvement in overall survival, 36.6 months versus 28.8 months, and a 36 percent reduction in the risk of death.
Longer follow-up is needed to more definitively determine whether there is an overall survival benefit for high-risk patients, acknowledged the study’s lead investigator, Dr. Gunnar Kristensen of the Norwegian Radium Hospital in Oslo. But, he continued, the current data suggest that, for these patients, bevacizumab “may be of clinical relevance.”
The results from the OCEANS and ICON7 trials—and results from a trial reported at last year’s ASCO meeting, GOG 218, which showed a nearly 4-month improvement in progression-free survival for women who received chemotherapy and bevacizumab as initial therapy for advanced ovarian cancer—are not yet enough to support using bevacizumab to treat ovarian cancer, said Dr. Ursula Matulonis of the Dana-Farber Cancer Institute.
The findings to date, she continued, “are certainly very exciting.” But given the potential serious side effects of bevacizumab, particularly bowel perforation, it’s important to proceed with caution. “Ideally, we would have a biomarker that would predict responsiveness to bevacizumab,” Dr. Matulonis said, “one that identifies an angiogeneic subtype that you could use to select patients who would benefit most.”
In a phase II clinical trial of the experimental drug cediranib, more than half of patients with a rare type of cancer called alveolar soft part sarcoma (ASPS) saw their tumors shrink. Results from 33 patients participating in the study were presented at the ASCO annual meeting in Chicago on June 6.
ASPS is a form of soft tissue sarcoma that strikes teens and young adults. It usually develops in the muscle or other soft tissue of the arms, legs, pelvic region, or head and neck area. Because ASPS tumors typically cause no pain and grow slowly, they are often not discovered until the cancer has reached an advanced stage. There is currently no accepted standard of care for patients with advanced ASPS.
Cediranib interferes with several proteins that help tumors develop the new blood vessels they need for continued growth and spread throughout the body, a process known as tumor angiogenesis. NCI’s Division of Cancer Treatment and Diagnosis (DCTD) and Center for Cancer Research launched the study at the NIH Clinical Center based on the observation that ASPS tumors are highly dependent on angiogenesis, as well as on early findings from a British clinical trial of cediranib involving patients with different types of tumors, including some with ASPS. The research team was led by Dr. Shivaani Kummar of DCTD.
In the ongoing trial, patients take cediranib by mouth daily until their disease progresses or intolerable side effects develop. In the subset of data from 33 patients presented at ASCO, side effects included high blood pressure and diarrhea, both of which were manageable. Some of these patients were still taking cediranib after more than a year of treatment.
“It is unusual to see such high levels of tumor shrinkage in a cancer that traditionally has not responded to standard chemotherapy used for the treatment of sarcomas,” said Dr. Kummar. “These are exciting results that warrant further evaluation.”
The researchers are still recruiting new patients to this study, and they are planning a multicenter follow-up study that will compare cediranib with sunitinib, another angiogenesis-blocking drug.
Positive preliminary results from an international clinical trial evaluating the use of additional radiation therapy for early-stage breast cancer were presented at the ASCO annual meeting last week. The risk of cancer recurrence was lower among women in the study who received additional radiation to nearby lymph nodes than among women who did not, according to interim results from the trial.
The National Cancer Institute of Canada led the randomized phase III study, called MA.20, with participation from NCI’s Clinical Trials Cooperative Group Program. Most of the patients enrolled had early-stage disease that had spread to nearby lymph nodes (node-positive) or were at high risk of a recurrence based on the size of their primary tumors. The vast majority of the patients were node-positive, meaning they had one to three lymph nodes with evidence of cancer, Dr. Timothy Whelan of McMaster University in Ontario explained in his presentation. All patients had breast-conserving surgery followed by chemotherapy or endocrine therapy.
Overall, after a median follow-up of more than 5 years, the women who received whole-breast irradiation as well as additional radiation to the nearby or regional lymph nodes, called regional nodal irradiation (RNI), had a statistically significant improvement in disease-free survival compared with the women who had received whole-breast irradiation without RNI.
The study’s primary endpoint was overall survival. The interim results showed an overall survival improvement among the RNI group compared with the non-RNI group, but the improvement was not statistically significant. (The 5-year overall survival rates were 92.3 percent versus 90.7 percent, respectively.) Whether this will change as the study continues remains to be seen.
The additional treatment came with additional side effects, including radiation dermatitis, pneumonitis, and lymphedema, Dr. Whelan reported.
Based on the findings, Dr. Whelan recommended that women with one to three positive nodes should be offered RNI, “provided that they are made aware of the associated toxicities.”
During a discussion of the results at the meeting, Dr. Thomas Buchholz of the University of Texas M. D. Anderson Cancer Center noted that the group of women who could be considered candidates for this treatment is heterogeneous. Not all patients with one to three positive lymph nodes “have the same risk of residual regional disease and, therefore, would not [all] receive the same benefit from this procedure,” he explained.
Dr. Buchholz also said that additional data were needed before he would consider offering the treatment to certain patients, including those who may have more favorable prognoses. Biological markers for identifying and distinguishing these subgroups are needed, he added.
An analysis of patients at a large Chicago-area hospital found that using a patient navigation service dramatically improved patient compliance with appointments for cancer radiation therapy. Results of the study at John H. Stroger Hospital of Cook County, which serves an urban, largely medically underserved population, were presented in a poster session at the ASCO annual meeting on June 4.
Researchers compared patients who were provided access to a patient navigation service (case patients) with those who were patients prior to the institution of such a program (control patients). Patients were matched on the basis of tumor site, disease stage, race, sex, and age. In addition to comparing case and control patients, the researchers also examined appointment compliance among case patients before and after the patients began using the navigation service. The service helped patients obtain assistance for transportation, child care, insurance, housing, education, and support for emotional needs.
The results showed that case patients with breast cancer were more likely to keep their appointments after receiving navigation assistance, with missed appointments dropping from 18 percent before assistance to 3 percent afterward. The number of patients with any cancer who kept all appointments rose from 24 percent before navigation assistance was offered to 36 percent, whereas the proportion of patients not completing their scheduled course of radiation therapy for nonmedical reasons fell from 19 percent to 6 percent.
Missed appointments can delay or compromise treatment, potentially leading to poorer outcomes, explained the study’s lead investigator, Dr. Elizabeth Marcus, adding that regardless of insurance status, one of the most common reasons for missed appointments was a lack of transportation. “It was often just an inability to get there,” she said.
In addition to demonstrating the value of patient navigation services, Dr. Marcus said the study showed that “having insurance doesn’t necessarily mean patients always have access to care.” She explained that trial participants will continue to be followed to determine whether improved appointment compliance improves survival, as well as to analyze the cost effectiveness of the navigation services.
The Illinois division of the American Cancer Society funded the study.
NCI Cancer Bulletin for June 14, 2011 - National Cancer Institute
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