Just In... Meeting News
Key news updates from recent oncology and hematology meetings.
Tuesday, January 27, 2015
BY ED SUSMAN
SAN ANTONIO – Aromatase inhibitor-related musculoskeletal syndromes -- not often mentioned in pivotal clinical trials -- affect more than half of women taking the drugs to prevent breast cancer recurrence, according to data reported at the San Antonio Breast Cancer Symposium.
“These symptoms occur frequently and we really have no good therapies for treating these women,” Janine Lombard, MBChB, a specialist consultant in oncology at Calvary Mater Hospital in Australia and lecturer at the University of Newcastle, Australia, said in an interview at her poster study.
The symptoms that are now considered part of the aromatase inhibitor musculoskeletal syndrome include arthritis, arthralgia, myalgia, carpal tunnel syndrome, joint stiffness, and paresthesia. “Arthralgia and other joint- related symptoms are common in menopausal women but are also a significant toxicity of aromatase inhibitors and are the most common cause of treatment discontinuation,” she said.
“In the study, those patients who developed the syndrome typically did so within the first eight weeks of therapy. However, the syndrome may also represent a persistent problem, as symptoms worsen from six to 24 months after starting.”
Many Treatment Options Tried
Treatment for these symptoms remain suboptimal, she said, and because of that, is also varied. For the study, questionnaires were sent to the Breast Cancer Network Australia Review and Survey Group, with 370 usable responses returned, which detailed the types of therapies used in attempts to mitigate symptoms.
The patients tried over-the-counter medications – most frequently paracetamol (acetaminophen) -- as well as various physician-prescribed pharmaceuticals and non-medical treatments as tai chi, with an overall success rate of 27 percent, Lombard said.
Doctors most often prescribed anti-inflammatory agents – to about 22 percent of patients -- and these treatments were deemed effective in 13 percent of patients; in another five percent, patients were unsure if the treatment was of any help and in four percent of the cases patients reported that the drugs were of no help.
Clinicians also prescribed codeine, morphine, vitamin D, corticosteroid injections, prednisone, paracetamol, and other treatments such as bisphosphonates, as well as duloxetine and amitriptyline and other antidepressants.
When patients went to the pharmacy for over-the-counter treatments, their choices were more varied but not much more successful. The first choice in over-the-counter treatment was found to be paracetamol, selected by 47 percent of patients. Thirty percent of these treatments were reported as being effective; patients said they were unsure of the effectiveness in another eight percent; and about 19 percent said there was no impact on reducing the symptoms.
Over-the-counter anti-inflammatory agents worked for about 17 percent of the patients, but six percent said they were unsure of a benefit and seven percent said there was no benefit.
Other over-the-counter medications included fish oil, glucosamine, vitamin D, krill oil, ibuprofen, chondroitin, aspirin, emu oil, magnesium, calcium, rose hips, and a variety of other herbs and/or nutrients.
Among the non-drug interventions tried, massage therapy was felt to be effective in 17 percent of the 24 percent of people who tried it; yoga in 10 percent of the 16 percent of those practicing that; acupuncture in seven percent of the 11 percent of people who tried it; and tai chi in three percent of the 3.5 percent of patients who used that. Other options tried to even less success were general exercise, physiotherapy, Bowen therapy (a form of hands-on holistic pressure), osteopathy, Feldenkrais (reducing pain through self-awareness), reflexology, and trigger point injections.
‘Huge Unmet Need’
“There is a huge unmet need for treatment for these musculoskeletal side effects from aromatase inhibitors,” Lombard said. “Women use a number of interventions to manage aromatase inhibitor musculoskeletal syndrome, but their efficacy appears limited.”
These musculoskeletal complaints may have been a major factor in women discontinuing treatments, she noted. About 26 percent of the patients in the study took aromatase inhibitors for less than a year. About 64 percent stayed on the drug for one to five years and 10 percent for more than five years.
A total of 33 percent of the women in the study said they considered stopping aromatase inhibitor therapy because of joint symptoms and 27 did discontinue treatment – and 68 percent of those women reported stopping because of musculoskeletal problems.
When they stopped taking their originally prescribed aromatase inhibitor, about half refused to try another treatment, and about 17 percent switched to tamoxifen.
Similar in U.S.
Although the study involved women in Australia, the situation is pretty much the same in the United States, said Coy Heldermen, MD, Assistant Professor of Medical Oncology at the University of Florida, Gainesville.
“This is a common problem with my patients,” he told OT while reviewing the poster. “There is a lot of testing and a lot of switching of therapies related to patients with these musculoskeletal problems. Everything that the Australian researchers have described is mirrored in my clinical experience as well,” he said.
“In the early studies of aromatase inhibitors, the problem with musculoskeletal syndrome did not seem to be an issue,” Lombard noted. “We don’t know why that is, but in our clinical experience 80 percent of women who discontinue treatment report that this syndrome is a factor.”
Still, she said, many of the symptoms – joint pain, fatigue, genitourinary symptoms, hot flushes, depression, headache, and anxiety – are similar to what 50 percent of menopausal women without breast cancer report as well. So since her patients are informed about what possible adverse events might occur, it could be that they are noting symptoms that may just be related to menopause and not the treatment, Lombard acknowledged. However, most of the women who described the symptoms said they had begun with the onset of treatment or that the complaints worsened when they began treatment with aromatase inhibitors.
Finding an effective treatment is important, because aromatase inhibitors have been shown to have superior efficacy over tamoxifen in disease-free survival and even overall survival, Lombard said. She noted that two thirds of women with early breast cancers have hormone receptor positive disease and, therefore most of them would benefit from at least five years of adjuvant endocrine treatment; and some high-risk patients would receive further benefit from 10 years.
In conducting the survey, the researcher team emailed 2,390 members of Breast Cancer Network Australia in April 2014, seeking information about women who had been diagnosed with early breast cancer, defined as Stage I-III since 2007 and had used aromatase inhibitors in the past or were currently taking the drugs. The 45-question survey included demographics, use of aromatase inhibitors and tamoxifen, clinical manifestations and risk factors for musculoskeletal complaints, reasons for discontinuations and efficacy or intervention used for treatment of symptoms.
There was no response from 75 percent of the requests; and 10 percent of those who did reply failed to meet the study criteria, leaving 15 percent of the responses for analysis. About 81 percent of the patients responding reported musculoskeletal complaints, most often related to the feet (68%); hands or wrists (65%); knees (62%); hips (56%); shoulders or elbows (49%); back (46%), or neck (3%). Many patients reported multiple sites of joint pain.
Lombard did caution, though, that one of the limitations of the study was that small number of responses meant that the numbers in the individual interventions was also small, making it difficult to generalize.
Monday, January 26, 2015
By Ed Susman
SAN ANTONIO – Despite multiple clinical trials that show that a shorter course of high-dose radiation in early-stage breast cancer is at least as good as longer conventional radiation, the uptake of the more patient-friendly treatment is moving at glacial speed, researchers reported at the San Antonio Breast Cancer Symposium.
And a possible reason for the slow adoption of hypofractionated whole breast irradiation could be caused by the drag of financial considerations, said Yvonne Mowery, MD, PhD, a resident physician in radiation oncology at Duke University Medical Center.
She and her colleagues found that from the time the first studies were published showing non-inferiority and similar cosmesis from hypofractionated regimens until 2011 – the last year data were available -- less than 20 percent of patients with early invasive breast cancer who opt for breast-conserving surgery receive hypofractionated treatments.
Academic centers led the way for use of hypofractionated regimens, gaining ground in each year until representing about 20 percent of the eligible women in 2011, Mowery said in an interview at her poster study. But to be out in front meant that these centers had a very low bar to jump: Barely 10 percent of the patients at community facilities were offered hypofractionated radiation; about 15 percent of the comprehensive community cancer centers treated patients with the hypofractionated regimens.
Three Weeks of Therapy vs. Five to Six
With hypofractionated regimens, patients are given higher doses of radiation in a shorter period of time – about three weeks of therapy compared with five to six for conventional radiation. But If there are no outcome differences as far as disease control and cosmesis are concerned, financial concerns may be at the heart of why hypofractionation has not gained more of a treatment foothold, Mowery said.
“With hypofractionation there are fewer treatments, and with fewer treatments there are fewer payments. It is a financial incentive to the hospital but not necessarily to the physician like myself who works at a hospital. In private practice it might make a financial difference. Academic institutions have less of a financial motivation even accounting for other factors. But even the 20 percent utilization at academic institutions is still low.”
The study’s principal investigator, Rachel Blitzblau, MD, PhD, Assistant Professor of Radiation Oncology at Duke, added: “That is potentially a $3,000 to $5,000 difference per patient.”
Still, she noted, it’s not that there aren’t legitimate possible concerns about a move to hypofractionation: “With hypofractionation and the larger dose per day, it has been tradition and dogma in the radiobiology world that the larger the dose, the higher the chance of toxicity. So people are afraid of fibrosis and that kind of thing when higher doses are applied to larger breasts. I don’t necessarily believe that any more. Some people say they actually see better cosmetic outcomes with a larger dose per day,” she said.
And, Mowery said, specialists may also be reluctant to fix a system that isn’t broken. “For more than 30 years, conventional radiation has worked very well in preventing recurrence in patients undergo breast-conserving surgery with this early stage invasive breast cancer. Conventional fractionalization has been standard for a long time and it is hard for people to change.
“I think people sometimes get nervous when something has been working really well and then it is scaled back. They don’t know what the larger dose per day will mean for potential cardiac toxicity in the long term. It takes a long time for cardiac toxicity to show up, and we haven’t followed these women long enough to see a difference in that. I think there is some natural wariness.”
On the other hand, randomized clinical trials such as the Ontario Clinical Oncology Group study determined that after 10 years of follow-up, no significant differences were found between the groups in the distribution of causes of death, including cardiac deaths. “You could make the argument that long-term data have not been released yet, but at this point we have 10-year data from three different trials so you really can’t make that argument,” Mowery said. She cited results from the landmark Royal Marsden trial and the START A and B trials conducted in the United Kingdom that show similar outcomes for hypofractionated and conventional fractionated regimens.
She also said that patients appear to prefer the 15 to 16 radiation fraction performed in three weeks compared with conventional regimens that are given in 25 fractions. “A lot of patients come to Duke for a second opinion and then they go back to their community centers. Many of them would rather stay at Duke for three weeks and then have to undergo five to six weeks of treatment with conventional fractionation back home at their community center. The results are non-inferior and, if anything, the cosmetic results are better in the patients who received hypofractionated regimens than conventional regimens.”
Also commenting on the study at the poster, Mylin Torres, MD, breast cancer specialist at Emory University, where she is Associate Professor of Radiation Oncology, said: “We do see a better cosmetic outcome with hypofractionated radiation in these patients. I think there has been a greater uptake of the regimen at academic facilities. There may be a bit of a financial incentive in doing the conventional radiation. It does mean more treatments and that means greater reimbursements.”
For the retrospective, population-based cohort study, the researchers used the National Cancer Data Base with information from 2004 to 2011, including adult women with early-stage, node-negative invasive breast cancer who underwent breast-conserving surgery and received adjuvant breast radiotherapy.
The regimens included (1) accelerated partial breast irradiation at a dose of 38 to 40 Gy in one to 10 fractions; hypofractionated whole breast irradiation with a dose of 40 to 56 Gy in 13 to 16 fractions; and conventional whole breast irradiation with a dose of 50 to 66 Gy in 23 to 28 fractions.
The researchers reviewed the patterns of treatments among 217,789 patients. Accelerated partial breast irradiation was used by 2,679 patients (1.2% of the total); hypofractionated radiation was employed in 11,444 patients (5.3% of the total), and conventional fractionated irradiation was used in 203,666 patients (93.5% of the total).
Community cancer programs handled 25,209 patients; 133,411 patients were seen in comprehensive community cancer programs; and 56,767 patients were treated at academic/research centers.
In 2004, the first year of the analysis, virtually all women who had breast-conserving therapy and opted for adjuvant radiation therapy were given conventional fractionated regimens. By 2011, that had fallen to about 82 percent of the treatments.
Use of hypofractionated radiation regimens rose slowly over that seven-year period to about 16 percent of patients. The accelerated irradiation procedure failed to gain any traction and remained at about one percent of patients across the time period.
Older Patients Benefited Most
The greatest beneficiaries of accelerated use of hypofractionated irradiation were the oldest of the patients in the study, the researchers reported. But even in the 11,316 patients who were 81 to 90 years old, just 35 percent received hypofractionated treatment regimens. There were just 707 women in the age 18-to-30 group, but almost none of them were offered the hypofractionated treatments.
Multivariable logistic regression analysis in 2011 showed that the chance of receiving hypofractionated radiation therapy in an academic institution was 3.06 times that of being treated in the community hospitals, and 1.78 times more likely in a comprehensive community cancer center. If the patient was age 50 or older, there was a 2.37-fold greater chance of receiving hypofractionated regimens than if the patient was age 18 to 30.
“Utilization of hypofractionated whole-breast irradiation in the United States is rising but remains low despite level 1 evidence showing its non-inferiority to conventional fractionated radiation,” Mowery said. “Treatment at an academic center, older patient age, hormone receptor positivity, smaller tumor size, and rural residence are associated with hypofractionated whole-breast irradiation use in multivariate analysis.”
The researchers suggested that “given the advantages of hypofractionated whole breast irradiation in terms of patient convenience and potential health care system costs, further research is indicated to explore disparities in hypofractionated whole breast irradiation utilization in the United States and to guide education of breast cancer providers.”
Sunday, January 25, 2015
By Robert H. Carlson
San Antonio--Here's a switch: In Japan, where obesity is rare, it is lower body mass index (BMI) that correlates with worse prognosis in patients with early-stage breast cancer. In Western countries, of course, higher BMI and obesity are associated with worse prognosis.
The researchers, from the Exploratory Oncology Research and Clinical Trial Center of National Cancer Center Hospital East in Kashiwa, Chiba, reported their findings in a poster presentation at the San Antonio Breast Cancer Symposium, speculating that there may be an optimal BMI in patients with early breast cancer.
The retrospective analysis used data from the prospective Phase III N-SAS BC02 and BC03 adjuvant chemotherapy trials with 1,756 patients with early breast cancer. The principal investigator was Yoichi Naito, MD, of the Division of Experimental Therapeutics.
The researchers hypothesized that because low BMI is common in Japan and obesity is rare, a Japanese cohort would be suitable to assess the impact of low BMI on survival in breast cancer. Analysis from an earlier Phase IIl trial, JFMC 34-0601, suggested that low BMI was associated with decreased overall response to neoadjuvant endocrine therapy with exemestane (Takada et al: The Breast 2012;1:40-45).
In the study presented here, the patients’ median age was 56, 71.2 percent were ER-positive, 9.7 percent had HER2 overexpressed, and lymph node metastases were seen in 76 percent.
The mean BMI value of all 1,756 patients was 23.3; about 33 percent of patients had a BMI of less than 22, 4.8 percent had a value lower than 18.5, and only 4.6 percent had a BMI over 30.
Univariate analysis showed that a BMI under 27 was significantly associated with worse prognosis compared with over 27, with a hazard ratio of 0.55. Multivariate analysis showed a hazard ratio of 0.61.
Making a non-so-subtle point, the poster presentation included a 2003 chart of 16 countries in the Organization for Economic Co-Operation and Development (OECD) showing the percentage of population with BMI scores greater than 30 –i.e.., being technically obese. The weighted average was 14.1 percent. Japan and South Korea were had the lowest, at 3.2 percent. The U.S. topped the list, with 30.6 percent of the population at a BMI greater than 30.
Improving on TNM Predictive Ability
Another poster study at the meeting attempted to improve on the venerable TNM (tumor-node-metastasis) staging system; that classification has served oncologists well for decades, but the thought was that the impact of new prognostic factors would undoubtedly improve the system's predictive ability.
Researchers at Walter Reed National Military Medical Center developed a staging system that incorporated several new risk factors into the TNM system, using the Ensemble Algorithm of Clustering of Cancer Data (EACCD). Six different prognostic factors were sequentially integrated into the TNM system to show their combined impact on 10-year survival rates for breast cancer patients: tumor grade, estrogen receptor (ER) and progesterone receptor (PR) status, age at diagnosis, racial/ethnic group, and histological tumor type.
The researchers applied the algorithm to a SEER database of approximately 132,339 cases of female breast cancer diagnosed between 1991 and 2000. When survival rates were generated for every combination of prognostic factors, it was shown that the rates for some tumors with the same TNM stage varied greatly.
For example, a woman traditionally classified as having stage IIA disease by TNM alone could have a 10-year survival rate anywhere from 75 to 96 percent with all the possible combinations of TNM plus the six new factors.
Looked at another way, women with a 10-year survival rate of 90 percent could be classified as having TNM stage IA to IIIC, depending on the other variables.
First author Jigarkumar Patel, MD, a general surgery resident in the Department of Surgery at Walter Reed and a captain in the US. Navy, offered another example: “According to traditional TNM staging, a woman with T1, N2, grade 1, ER-positive, PR-positive disease who is under 50 years of age would be stage IIIA, but based on our algorithm, she would have a 10-year survival rate of 90 percent, which really should qualify her for stage I.”
Patel called this “deconstructing” TNM--“These added prognostic factors truly affect what these outcomes are, which we already know to be true. The algorithm shows it into a way we can all understand.”
He added that integrating combinations of prognostic factors revealed frequent crossover pf stage groups at 10 years, a violation of a stating system that could impact the interpretation of clinical trials.
Chemotherapy, but Not Hormone Therapy, Associated with Weight Gain
Contrary to what some oncologists tell their breast cancer patients, and what some women expect, hormone therapy does not in itself cause weight gain, according to a study by researchers at Johns Hopkins Bloomberg School of Public Health.
But the study did show that weight gain occurred at a faster rate in breast cancer survivors than in women who are at high risk of breast cancer due to family history, and was particularly rapid in cancer patients who were treated with chemotherapy and used statins.
“But not in women treated with surgery and/or hormonal therapy alone,” said first author Amy Gross, MHS, a doctoral candidate in the Department of Epidemiology.
The 303 breast cancer survivors and 307 cancer-free women in the study were matched for age and menopausal status, and median baseline BMI did not differ significantly between the two groups.
Survivors treated with chemotherapy gained on average 5.58 more pounds than cancer-free women, whereas those treated with surgery and/or hormone therapy alone did not gain significantly more, Gross said.
Compared with cancer-free women, survivors diagnosed within the past five years were twice as likely to gain at least 11 pounds during follow-up.
Gross noted that oncologists she spoke with at the poster session were surprised that hormone therapy alone was not associated with significant weight gain. “Some oncologists tell their patients to expect to gain weight when starting tamoxifen or an aromatase inhibitor, but they should tell their patients not to expect to gain weight just because they are on hormonal therapy.”
PR+ a Plus for Prognosis
A study from Belgium showed that normal-weight postmenopausal patients have a reduced risk of developing distant metastases and of breast-cancer related death if the tumor is PR-positive versus PR-negative.
For overweight or obese patients with PR-positive tumors there was only a non-statistically significant trend toward lower risk, and then only for the first five years following diagnosis, said first author Kathleen Van Asten, a doctoral student at Katholieke Universiteit (KU), Leuven. The findings were based on data for 3,227 women over age 50 diagnosed with primary, operable breast cancer at the university's hospitals between 2000 and 2012. Median follow-up was 6.5 years.
The hazard ratio for breast cancer-specific survival was 0.22 for all women in the study with a BMI less than 25; 0.95 for women with BMI greater than 25; and 0.53 for BMI over 30. For luminal B-like disease, the hazard ratios were 0.14, 1.02, and 0.61, respectively.
“This is not what we expected, and we are investigating further,” Van Asten said.
“These added prognostic factors truly affect what these outcomes are, which we already know to be true. The algorithm shows it into a way we can all understand.”
Sunday, January 25, 2015
By Ed Susman
SAN FRANCISCO – Patients with metastatic pancreatic cancer appear to have similar outcomes but less adverse events if they are given a reduced regimen of standard gemcitabine and nab-paclitaxel, according to data reported here at the Gastrointestinal Cancers Symposium (Abstract 366).
The meeting is co-sponsored by the American Gastrointestinal Association Institute, the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
“A less intense regimen of gemcitabine plus nab-paclitaxel maintains efficacy while significantly improving the toxicology profile and cost among patients with metastatic pancreatic cancer,” said Kavya Krishna, MD, a fellow in hematology/oncology at Ohio State University Comprehensive Cancer Center--Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.
“Instead of three weeks of treatment and one week off, we are treating patients every other week,” she said in an interview at her poster study. “We are reducing the amount of gemcitabine and nab-paclitaxel by one-third.”
In the Phase III clinical trial by Daniel von Hoff, MD, et al published in October in the New England Journal of Medicine (369:1691-1703) showing increased survival for combined gemcitabine and nab-paclitaxel, progression-free and overall survival times were 5.5 and 8.7 months, respectively. Survival times in the new study were 4.8 months for median survival and 11.1 months for overall.
“We are suggesting that our regimen is equivalent to the standard treatment. Patients seem to have a sustained response and we have patients on this therapy tolerate it well going to several cycles. We treat until there is disease progression or unacceptable toxicity,” Krishna said.
“The combination of gemcitabine and nab-paclitaxel in first-line treatment of metastatic pancreatic cancer has a modest survival advantage over gemcitabine alone, but adds significant toxicities and increased cost. Based on data suggesting that biweekly administration of gemcitabine-based combinations preserves efficacy and improves the toxicity profile, our institution adopted a modified regimen of gemcitabine plus nab-paclitaxel. We adapted the every-other-week regimen of giving gemcitabine from our clinical experience with patients who would skip a week and seemed to do as well as patients treated every three weeks before taking off one week. And there are clinical trials that indicate that-every-other-week nab-paclitaxel is effective in treating diseases such as lung cancer.”
The regimen was better tolerated and resulted in less hematological toxicity (known to be a particular problem with gemcitabine)—“In the metastatic setting we have been using the every-other-week gemcitabine even before we adopted this regimen,” Krishna said.
“The most commonly used regimen is to treat with gemcitabine is on Days 1, 8, and 15 of a 28-day cycle. The gemcitabine plus nab-paclitaxel regimen uses the same treatment schedule. Now we administer gemcitabine plus nab-paclitaxel on Day 1 and Day 15. We have dose-delay and dose-reduction data but we didn’t record discontinuation data because it is a smaller patient population and most of the patients went off therapy because the disease progressed.”
Regarding the apparent increase in median overall survival pf 11.1 months, she said: “Another factor in this patient population was that they didn’t get beat up by the chemotherapy. They still had a pretty reasonable performance status so once they progressed they were able to go on to second-line and third-line therapies. That’s why the overall survival is so much better than progression-free survival.”
Not Ready to Use Routinely
Asked for his perspective, Tony Philip, MD, an attending physician in hematology/oncology at North Shore-Long Island Jewish Cancer Institute and Assistant Professor of Medicine at Hofstra North Shore-LIJ School of Medicine, said: “This study gives me another option if I had a patient who was older or frail and wanted to give a less-intensive chemotherapy regimen. However, I don’t think we have enough information now to use it routinely with people who are in good performance status.
“This is a single-institution study, and it is not compared with anything. I think we need to take these results with a grain of salt. There needs to be a prospective randomized trial comparing every-other-week treatment with three weeks on, one week off therapy.”
The researchers pointed out that a switch to an every-other-week regimen also results in substantial cost savings--an estimated $5,500 per patient per month of treatment. “That figure does not include the cost for growth factors used in treating neutropenia,” Krishna said. “Neulasta [pegfilgrastim] is pretty expensive too. In the clinical trial the rate of growth factor use was 26 percent, but in our experience with the every-other-week regimen, just eight percent of patients required growth factors.
“The combination of gemcitabine and nab-paclitaxel in pancreatic cancer is one of the most recent advances in pancreatic cancer treatment and has been shown to improve survival when compared with gemcitabine alone. But this improved survival comes with increased toxic side effects that can affect quality of life. We sought an alternative regimen that would prolong treatment effectiveness and reduce side effects.”
She and her colleagues identified 69 patients with pancreatic cancer who received the modified regimen of gemcitabine and nab-paclitaxel. Forty nine had previously untreated metastatic pancreatic cancer and the remaining 20 had either progressed on other chemotherapy treatments or had locally advanced or borderline resectable disease. The patients’ median age was 65.
Overall, less than two percent of patients had severe neurological toxicities compared with 17 percent in the previous Phase III study using the three-week-on, one-week-off schedule; 10 percent of patients had severe low white blood cell counts compared with 38 percent of patients in the Phase III study.
Gives Immune System Time to Recover
The study’s senior author, Tanios Bekaii-Saab, MD, Section Chief of Gastrointestinal Oncology at the James and Associate Professor of Medicine, explained that shifting to a regimen of every other week gives the immune system time to recover between chemotherapy sessions and results in less overall toxicity. It is also more convenient for patients since it means fewer visits to the infusion center to receive chemotherapy.
“Pancreatic cancer is an especially difficult diagnosis, so weighing the survival benefit of available treatments against how treatment side effects will impact a patient’s remaining life is a critically important part of the treatment planning process,” Krishna said.
Friday, January 23, 2015
BY ED SUSMAN
SAN FRANCISCO – Neoadjuvant chemotherapy plus radiation appears to allow a high percentage of pancreatic cancer patients deemed borderline resectable to safely undergo surgery – which leads to significantly extended overall survival -- researchers reported here at the Gastrointestinal Cancers Symposium (Abstract 360).
Even a few patients who are diagnosed with locally advanced pancreatic cancer – usually not considered eligible for surgical resection – can undergo successful resection, said Eric Mellon, MD, PhD, a resident in radiation oncology at H. Lee Moffitt Cancer Center and Research Institute.
“In our experience, whether a patient has borderline resectable pancreatic cancer or locally advanced pancreatic cancer status entering the treatment protocol, it is unimportant compared with whether patients undergo complete resection,” he said in an interview at his poster presentation. “Patients who undergo resection after treatment have the best prognosis.”
Among patients who were resectable after chemotherapy and stereotactic body radiation, about 50 percent were alive at 36 months compared with only about five percent who did not undergo surgery, he reported.
“About 10 to 20 years ago, all of the patients in this series would not have had surgery – they would have been doomed to die. The only way to cure someone with pancreas cancer is to get them to surgery. Our goal here is to treat these patients who are borderline resectable or even some of those who are locally advanced and get them to surgery.
“Some of those patients with locally advanced pancreatic cancer who were never going to get surgery before can be resected, probably because of treatment with FOLFIRINOX [fluorouracil, leucovorin, irinotecan, and oxaliplatin],” Mellon continued, adding that none of the patients with locally advanced pancreatic cancer who received gemcitabine-based chemotherapy responded sufficiently to undergo resection.
Goal: To Shrink the Tumor Enough to Get It Off the Superior Mesenteric Artery
In addition to the chemotherapy regimen, stereotactic body radiation is also used to further shrink the tumor, he explained. “The goal is to shrink the tumor enough to get it off the vessel – the superior mesenteric artery. If you have to clip the blood vessel and take out part of the artery to remove the tumor, it is considered unresectable.”
He said that attempts to perform surgery that would take out the tumor and then re-attach the artery segments generally have not been successful.
Mellon said that in the few cases in which locally advanced tumors have been reduced enough to permit surgery, the outcomes are encouraging: Of the 49 patients initially diagnosed with locally advanced pancreatic cancer, five of the patients or 10 percent had complete resection of their tumor. The small number of patients kept the results from achieving statistical significance, he noted.
“After six months of follow-up, none of those patients have died. None of them have even had cancer recurrence.” Two other patients went to surgery but could not be resected. The remaining 86 percent of these locally advanced pancreatic adenocarcinoma patients did not undergo surgery.
The Real Issue…
“The point we are trying to make here is that it is not important whether you come in with borderline resectable or locally advanced disease, the real issue is whether you got to surgery,” Mellon said. “If you get to surgery, you do so much better.”
Of the borderline resectable patients, about 50 percent got to surgery, and while the median survival is three years for the group who underwent the neoadjuvant chemoradiation, historically, the survival is better than that seen with upfront surgery, he said.
Study of the Two Schedules
Mellon said he is currently working on a study that compares the two schedules—i.e., upfront surgery versus surgery following neoadjuvant therapy.
He said that prospective, randomized data are necessary to change treatment guidelines. Moffitt is a member of the National Comprehensive Cancer Network (NCCN), which writes guidelines for treatment of cancer that are accepted worldwide. Mellon said that current NCCN guidelines suggest that neoadjuvant treatment be given to patients with borderline resectable pancreatic adenocarcinoma before surgery is attempted in these patients, but there are no data about which regimen is preferred for neoadjuvant therapy--“This may be one option.”
He said that the use of stereotactic body radiation therapy is emerging for use in pancreatic cancer in hopes of increasing the radiation dose to the cancer without causing radiation toxicity to nearby organs such as the duodenum and stomach.
And even if the neoadjuvant therapy fails to reduce the tumor enough to permit safe surgery, there are still benefits: “Local disease control is good after stereotactic body radiation therapy even if the cancer is never amendable to surgery,” Mellon said. “In patients who were not surgically resected, our one-year local control was 78 percent. However, the patients still die of metastatic disease.”
In his study, he and his colleagues reviewed all cases of non-metastatic borderline resectable or locally advanced pancreatic cancer patients who were treated by stereotactic body radiation therapy from 2009 to 2013 at Moffitt. Median follow-up from the start of chemotherapy was 14 months, and patients underwent induction therapy with gemcitabine, docetaxel, and capecitabine (GTX), FOLFIRINOX, or other gemcitabine-based regimens.
One week after chemotherapy ended, the patients underwent stereotactic body radiation therapy. Patients were prescribed stereotactic body radiation therapy in five5 equal fractions. Dose-painting techniques were used to increase the dose to areas of tumor-vessel abutment – a median of 40 Gy. Gross disease received a minimum dose of 30 Gy.
A median of seven weeks after radiation therapy – up to three months after radiation -- patients were reassessed for resectability. Of the 110 borderline resectable pancreatic cancer patients, 51 percent underwent resection with a three percent positive margin rate.
A total of 21 percent of patients did not go on to surgery due to progression to unresectable status on imaging; seven percent were unresectable at surgery; metastases was found in 14 percent of patients at surgery, and seven percent of patients were deemed medically inoperable due to performance decline during neoadjuvant therapy,
Mild acute radiation-induced toxicities, including Grade 1 and Grade 2 fatigue, pain, nausea, and diarrhea, were common but no toxicity prevented surgical resection.
Possible Selection Bias
Asked for his perceptive for this article, Tony Philip, MD, an attending physician in hematology/oncology at North Shore-Long Island Jewish Cancer Institute, said: “We need a randomized clinical trial to determine if neoadjuvant chemotherapy is really changing outcomes in pancreatic disease for patients who have borderline resectable pancreatic cancer--It may be that the patients who are selected for neoadjuvant therapy are simply better candidates for surgery and so these outcomes look better because of that selection bias.”
In a related study also performed by researchers at Moffitt, Omar Rashid, MD, JD, a complex general oncology surgery fellow, suggested that by following a multidisciplinary treatment pathway, more than half of patients with borderline resectable pancreatic cancer can undergo potentially curable surgery (Abstract 374).
“We looked at the clinical pathway that is used to assess these patients,” Rashid noted at his poster presentation “Right now how borderline resectable pancreatic cancer is treated in different parts of the country depends upon where the patients are, in terms of how they are staged and to what regimen is used.
“Some things are unique to Moffitt. We use a CT-scan, PET-scan and also endoscopy with ultrasound to image the patient,” he said. “Then everyone comes together – different surgeons, gastroenterologists, and the tumor board – and they decide if the patients are indeed borderline resectable. If they are, then we give them GTX and stereotactic body radiation therapy, and then re-stage the patient. If there is a chance of resection, we then take patients to surgery.”
The study showed that from 2006 to 2013, borderline resectable pancreatic cancer was diagnosed in 121 patients presenting at Moffitt. Of that group, 101 were entered into the study of the multidisciplinary clinical pathway assessment.
Rashid reported that about 93 percent of these patients were able to complete adjuvant therapy. The panel of doctors then determined that 55 (54.5%) of the patients were suitable for and underwent surgery. Of those who went to surgery, 53 (96%) had a complete resection of the tumor – an RO resection; and two patients had an R1 resection.
“One of the reasons we did so well, maybe,” Rashid speculated, “was that we were so selective at the beginning. Another might be the chemotherapy regimen – 81 percent of patients had a partial response, and 14.5 percent had a complete pathological response.”
Patients who were not resectable after therapy achieved a median 14-month overall survival compared with 33 months for patients who were able to have surgery. “We are not curing these people with surgery, but we are moving the curve more in that direction,” Rashid said.
Call for Prospective Intergroup Study
He said that a prospective study needs to be performed to test the various regimens: “It shouldn’t be that the treatment you get depends on where you end up. It should be based on data. The only way we will get that is if the pancreatic cancer Intergroup comes together and says, ‘Look, we are going to do this.’”
The three-day, which is co-sponsored by the American Gastrointestinal Association Institute, the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology, had approximately 3,400 attendees this year.