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Tuesday, April 15, 2014

BY KURT SAMSON

 

Asking bone marrow recipients to rate their breathing difficulties on a scale of 0 to 3 appears to identify lung involvement due to graft-versus-host disease (GVHD) and predict overall survival, including non-relapse mortality, researchers have found.

 

Reporting in the journal Biology of Blood and Marrow Transplantation (2014;20:337-344), a team led by Stephanie J. Lee, MD, MPH, Professor of Oncology at the University of Washington School of Medicine and Fred Hutchinson Cancer Research Center, conducted a prospective analysis of 1,591 visits by 496 patients at various treatment centers. The results showed a clear association between increased mortality among patients with worse breathing scores, but even those with less pronounced problems had shorter survival than those without any problems.

 

The study, part of the Chronic GVHD Consortium, included patients recently diagnosed with chronic GVHD as well as those who had had it for several years.

 

For marrow recipients, the likelihood of developing chronic GVHD is in the range of 30 to 50 percent, and of those who do develop it, about 15 to 20 percent have lung involvement, the team noted.

 

In 2005 the National Institutes of Health recommended testing lung function in patients with chronic GVHD, using both pulmonary function tests and symptom assessment, including a three-point questionnaire – 0 for no symptoms, 1 for shortness of breath walking up stairs, 2 for shortness of breath while walking on flat ground, and 3 for shortness of breath when resting or when oxygen therapy is necessary.

 

A comparison of survival rates with clinician- and self-reported lung function based on this technique revealed that a score of 3 was strongly associated with short survival, but that even patients with a score of 1 or 2 had worse outcomes than those with a score of 0.

 

The results showed that the questionnaire outperformed other tests typically used to assess lung function, including spirometry, lung volume measurement, lung diffusion capacity, and measurement of oxygen levels.

 

Pulmonary function test (PFT) data, including the higher lung function score (LFS) and obstructive physiology, were not associated with overall survival or non-relapse mortality, nor was a diagnosis of bronchiolitis obliterans syndrome (BOS).

 

In the study, lung function scoring was based on forced expiratory volume at 1 second (FEV1), forced vital capacity (FVC), and diffusing capacity for carbon monoxide (DLCO). Obstructive disease was defined as a decreased FEV1 (tested at <50%, <75%, and <80%) and FEV1/FVC of less than 0.70.

 

Obstructive physiology (FEV1<80%) was found in 184 patient visits, and 54 visits (6%) had FEV1< 50%.  BOS was reported on 122 visits. Median follow-up time was 20 months, with a range of 2.9 to 47.7 months. Median survival had not been reached by the time of the paper’s publication.

 

The researchers cautioned that there were limitations regarding inconsistent practices in performing the tests, and that of the 1,591 patient visits used in the analysis, only half had recorded PFTs.

 

Could Hasten Treatment

Use of the questionnaire scoring system could help physicians identify early GVHD lung problems and hasten treatment to reduce or manage symptoms, said Lee, who provides hematopoietic cell transplants for patients with leukemia and myelodysplastic syndromes.

 

“The results put us on notice to be more careful and attentive to lung symptoms in people with chronic GVHD,” she said in an interview. “A poor score can also serve as a reminder to make sure the patient has had a pneumonia vaccination and is taking other precautions to minimize ongoing loss of lung function.

 

“It is important that we pay closer attention to patients with poor lung scores. If we can identify patients when they first develop lung problems, we can try to intervene and prevent severe loss of lung function. Currently, physicians tend to focus on other health issues, but we need to look at the entire spectrum of this disease, and lung function needs more attention.”

 

Patients need to be asked directly about any breathing problems, she emphasized, although this can be difficult because lung involvement typically evolves slowly and patients often get used to symptoms or attribute them to other causes like not exercising, she said.

 

“Not all breathing problems can be attributed to GVHD, but the combination of chronic GVHD and lung symptoms is concerning. Patients with chronic GVHD should be asked at every clinic visit whether they have noticed any shortness of breath.”

 

She said that because the research team now has a large number of patients and stored blood samples, they are looking to collaborate with other investigators to better understand lung involvement in chronic GVHD.

 

“Researchers are searching for other ways to identify patients at higher risk of lung involvement as well as possible biomarkers in the blood,” she noted. There is a lot of activity in this field, especially for biomarkers, and there are a lot of leads.”

 

Questions Remain

What leads up to worsening lung function is unknown, added the study’s first author, Jeanne Palmer, MD, of the Blood and Marrow Transplant Program at the Mayo Clinic in Phoenix, Ariz.

 

How best to identify those who will develop pulmonary complications remains a subject of investigation, she said, and investigators are evaluating CT imagining modalities in this direction. There are also ongoing studies to evaluate the effect of early therapy among patients who show a decline in lung function.

 

In addition to improved screening to identify patients when they have subclinical disease, improved understanding of the underlying biology is also needed, she said.

 

“The basic takeaway message is that if GVHD is bad enough that a patient has pulmonary symptoms, it correlates with worse outcomes, and we need to identify these patients before they develop pulmonary symptoms.”

 

Greater Awareness Needed

Asked for his opinion for this article, Gerhard Carl Hildebrandt, MD, Medical Director of the Huntsman Cancer Hospital Blood and Marrow Transplant Program and Associate Professor of Medicine, at the University of Utah,  said the paper should help raise awareness of the potential for lung involvement in GVHD.

 

“This is a very important paper because it highlights the fact that the lungs are a potential target organ and confirms clinical observations of this issue over the long-term,” he said. “The study illustrates not only that these patients might be at risk, but that both patients and physicians to be more aware of the potential for lung involvement.”

 

He said most primary care physicians presented with a patient experiencing breathing problems typically assume that there is an infection, but they need to be aware that the lungs are sensitive to GVHD in transplant recipients for years after treatment. Physicians need to ask the appropriate questions and test patients for lung function, which will in turn provide more data for researchers and transplant centers.

 

“This simple questionnaire can provide primary care doctors with an easy way to ask patients about pulmonary symptoms and document potential GVHD lung involvement,” he said.

 

Regarding the study limitations, he also noted that the follow-up period was too short to gauge the full scope of the scoring system, and the lack of LFT data in about one-third of the trial subjects was also problematic.

 

“Many centers do ongoing serial lung function testing of all transplant recipients,” he said. “At our center we test them at three, six, 12, 18, and 24 months after a transplant, and then annually afterwards, and we also exclude infection at each visit. Some centers do not do, and a general advisory for annual testing would be welcomed.”


Monday, April 14, 2014

 

BY ED SUSMAN

 

HOLLYWOOD, Fla. -- An oral antidote to life-threatening toxicity from the rare situation of fluorouracil (5-FU) overdose or hypersensitivity appears to be highly successful, researchers reported here at the National Comprehensive Cancer Network conference.

 

The investigational drug, uridine triacetate, was successful in 97 percent -- 128 of 132 -- cases of 5-FU overdose caused by errors in dosing, infusion pump malfunctioning, or excess ingestion of oral 5-FU sources such as capecitabine, said Michael Bamat, PhD, Vice President of Research and Development at Wellstat Therapeutics Corporation in Gaithersburg, Md.

 

In the time since his poster study was presented in March, there have been five additional cases that came to the team’s attention, Bamat said in a follow-up interview, and the treatment has been successful in 133 of these incidents.

 

He explained that usual treatment for 5-FU toxicity has been best supportive care, but unfortunately, historical data suggest that this strategy is often unsuccessful. In his poster presentation at the NCCN meeting, researchers determined that in a historical control group of 40 patients with 5-FU toxicity, just four patients achieved a complete recovery. The rest of these patients died. Information on dosages and outcomes for the historical 5-FU overdose cases were obtained from publicly available reports, he noted.

 

“These clinical data illustrate the serious, debilitating, and life-threatening nature of 5-FU overexposure and the need for safe, effective antidotal treatment,” he said in the interview.

 

Very Rare, but Accidents Do Occur

Asked for her opinion, Edith Perez, MD, Deputy Director at Large at the Mayo Clinic Cancer Center in Jacksonville, Fla., said, “The risk of 5-FU overdose is extremely low. All chemotherapy units should have carefully outlined procedures to prevent incorrect doses of chemotherapy being given to patients.”

 

Nevertheless, accidental overdoses of 5-FU occur. Bamat cited National Institutes of Health estimates that 275,000 cancer patients are treated with 5-FU every year, and that 8,250 of these patients develop serious toxic reactions and that more than 1,300 patients die each year from 5-FU overexposure.

 

He said that about 60 percent of the cases that have been treated with uridine triacetate were caused by miscalculation or mismanagement of the intravenous delivery. Because 5-FU is administered at or near its maximum tolerated dose over one to four days, life-threatening or lethal toxicity can be caused by these pump-related errors, he said.

 

In addition, there are other patients who have dihydropyridimine dehydrogenase (DPD) deficiency and other forms of 5-FU elimination or hypersensitivity that can also result in serious or lethal toxicity following standard doses of infusional 5-FU or oral capecitabine. For example, unusual susceptibility to 5-FU can result in severe and sudden onset cardiac and/or neurological toxicities, he said, noting that 10 of the patients treated in his case series have been found to have DPD deficiency. Six children were included in the study.

 

Over-ingestion of capecitabine has also been a cause of overdose, including some cases in which patients attempted to commit suicide by ingesting capecitabine in lethal amounts.

 

Uridine, Bamat explained, is a direct biochemical antidote for 5-FU poisoning, but the drug has poor oral bioavailability, and complications during its infusion preclude use of uridine itself as a viable antidote. Hence, the researchers developed uridine triacetate as an orally available prodrug of uridine. Uridine triacetate is rapidly converted to circulating uridine by deacetylation.

 

The agent is administered at a dose of 10 grams every six hours for 20 doses in adults and at an equivalent dose of 6.2 grams/m2 every six hours for 20 doses. Treatment with uridine triacetate was initiated seven to 96 hours following the end of treatment with fluorouracil.

 

Based upon data collected to date, uridine triacetate appears to provide clinical benefit to patients even in cases where a lethal outcome otherwise would have been expected,” he said.

 

The patients in the study were treated after their physicians contacted the company to use the drug in a Food and Drug Administration-approved expanded access protocol for emergency use. Uridine triacetate was administered seven to 96 hours after 5-FU treatment was halted.

 

About half the patients were able to resume their chemotherapy regimens within three weeks after overexposure, Bamat reported. In addition, treatment with uridine did not appear to cause serious adverse events. The adverse events that did occur were considered mild, and many of the patients treated with uridine triacetate had no adverse events at all.

 

Uridine triacetate had previously received Orphan Drug designation as an antidote to treat patients at risk of excess 5-FU toxicity from both the Food and Drug Administration and the European Medicines Agency. Bamat said the company expects to file a New Drug Application for uridine by the end of the year.

 

A Phase III study is not possible in a treatment that is based on emergency overdose, he added. “When we submit our application for approval of uridine triacetate it will include the number of patients treated and their outcomes. We are continuing to treat patients under the expanded access program.”


Friday, April 11, 2014
 

BY ROBERT H. CARLSON

 

NEW YORK -- ATRA/ATO is the new standard of care for non-high risk patients with acute promyelocytic leukemia (APL), and overall survival rates with the regimen are over 90 percent, even without chemotherapy. But the incidence of early death during induction therapy is still high, and the development of APL differentiation syndrome, although rare, can be fatal if not treated immediately upon suspicion.

 

APL is clearly one of our success stories,” said Charles Schiffer, MD, Professor of Medicine and Oncology, and Interim Chair of the Department of Oncology at Karmanos Cancer Institute in Detroit, moderator of a session on leukemia here at the recent International Congress on Hematologic Malignancies.

 

 In introducing Martin Tallman, MD, Chief of the Leukemia Service at Memorial Sloan Kettering Cancer Center and Professor of Medicine at Weill Cornell Medical College, Schiffer said Tallman would describe how he treats APL, “but also remind us what not to do, because the greater tragedy is when you mess things up in someone who has a potential 80 or 90 percent cure rate.”

 

Tallman said the complete remission rate in general is indeed approximately 90 percent among patients with APL, and that ATRA/ATO – all-trans retinoic acid and arsenic trioxide – is the standard of care. But among that 10 percent who do not have a complete remission, approximately 60 to 70 percent will die from intracerebral or gastrointestinal bleeding, and 30 percent from infection.

 

In addition, that 90 percent complete remission rate is from large cooperative group trials, whereas population-based studies that include every patient diagnosed show an early mortality rate of 20 to 30 percent – for example, this one for which he was senior author (Park et al: Blood 2011;118: 1248-1254). Early death rate, and not relapse, has emerged as the single most important limitation to cure for the majority of patients,” Tallman said.

 

He reviewed the basics of APL:

·    It comprises 10 to 15 percent of adult acute myeloid leukemia (20-30 percent in Hispanics);

·    The overwhelming majority of patients with APL present with leukopenia;

·    APL is associated with life-threatening coagulopathy;

·    Almost every patient with APL has a (15;17) translocation;

·    APL cells are uniquely sensitive to anthracycline; and

·    Every APL patient has the PML-RAR-alpha fusion transcript associated with the t(15;17).

 

But the most distinguishing features, he said, are that these cells undergo differentiation to mature granulocytes with ATRA, and apoptosis with ATO. It's interesting that at a time when in most hematologic malignancies researchers are searching for better prognostic factors, and molecular prognostic factors are becoming more important, in fact the opposite is occurring in APL,” Tallman said.

 

We have as the major prognostic factor simply the peripheral white blood cell count,” and age is the other major prognostic factor. Platelet count is not seen today as critical, he said, and FLT3-ITD status has no prognostic importance.

 

Reduce Early Death with Early ATRA

It became apparent very early in the experience with ATRA that it reverses coagulopathy quite quickly -- in a median of about four days, Tallman noted.

 

Then why is the early death rate still a problem, since ATRA has been available for almost 20 years? And will early administration of ATRA reduce the death rate from bleeding? Time to ATRA administration appears to be a major reason.

 

In a study of time of ATRA administration for which Tallman was senior author (Altman et al: Leukemia Res 2012; 37: 1004-1009), ATRA was ordered for only 32 percent of patients on the day APL was suspected, in 33 percent one day after APL was suspected, and almost 20 percent of patients two or more days after. Since ATRA was received by 90 percent of patients on the day it was ordered, the critical delay was not in the length of time from ordering to time of administration but rather in ordering the drug, Tallman explained.

 

And there is no doubt that ATRA delay is related to risk of bleeding, he said: It is now recommended that ATRA be started at the first suspicion of the disease, based on clinical history and review of the peripheral blood smear, but before a bone marrow [biopsy] is done and before the diagnosis is confirmed. Many people now feel that ATRA should be administered in the emergency room, so it's important that ER doctors recognize APL.”

 

Tallman described a unique complication to ATRA exposure, the APL differentiation syndrome, which also calls for immediate treatment. Before diagnosis of the syndrome is even established, maintain vigilance, and give dexamethasone at 10 mg twice daily at the earliest symptom or sign, he said.

 

Stop ATRA or ATO if the syndrome is severe, and then resume at the resolution of all symptoms and signs under the cover of steroids.”

 

Evolution in Induction Strategies

There has been an evolution in induction therapy away from chemotherapy and toward the administration of ATRA and ATO, Tallman said, citing no less than six major cooperative studies using ATRA with little or no chemotherapy, showing complete remission rates of 89 to 100 percent, and overall survival rates of 89 to 99 percent.

 

He cited another study, which he said pointed to a regimen that could be used practically, outside the context of a clinical trial: Patients in the Australasian Leukemia and Lymphoma Group APML4 study (Iland et al: Blood; 2012;120: 1570-1580) received ATRA/ATO, and idarubicin, along with prophylactic prednisone for induction, while consolidation consisted of only two courses of therapy with ATRA/ATO, with no additional chemotherapy. Maintenance was ATRA on days 1-14 of a 90-day cycle, and 6-mercaptopurine and low-dose methotrexate on days 15-90, repeating the cycle for two years. Patients with low-, intermediate-, and high-risk disease had two-year relapse-free rates of 100, 98, and 92 percent, respectively.

 

Another trial, the GIMEMA/SAL/AMLSG-APL0406 study, also showed very successful results, with little or no chemotherapy for low-risk patients: Lo-Coco F et al. N Engl J Med 2013; 369:111-121  OT 8/25/13 issue). The overall survival rate at approximately four years was 98.7 percent for patients receiving ATRA/ATO.

 

Tallman said he enrolls patients on a clinical trial for induction if one is available. Otherwise he uses ATRA/ATO for low-risk patients, adding idarubicin for high-risk patients as in the Australian study. ATRA/idarubicin for both low- and high-risk patients is still a reasonable induction approach as well,” he said.

 

And, he recommends intrathecal central nervous system prophylaxis for high-risk patients.

 

‘Tricks’ That Work

Tallman offered his “tricks of the trade” in APL induction:

 

First, he said, there is no evidence that therapy need be modified based on additional cytogenetic abnormalities, whether the APL is therapy-related, FLT3 mutations, CD56, PML isoform, or morphology.

 

And there is no need for a bone marrow biopsy on day 14, he said, and it may not even be needed once a patient achieves complete remission. If a patient survives induction, there is no primary resistance in this disease. Everybody achieves a remission if they survive induction. And there is no prognostic importance of any cytogenetic abnormality or molecular findings, when first remission is achieved. So I'm not sure we need to be doing any complete remission bone marrow. ”

He recommends aggressive platelet transfusion and fibrinogen replacement, but said a central venous catheter should not be placed. Leukapheresis is generally not recommended, and myeloid growth factors are not needed.

 

He reiterated the need to watch for APL differentiation syndrome and to give dexamethasone to high-risk patients or at the earliest sign or symptom, such as shortness of breath, cough, or pleural effusion.

 

An exciting development in the field, he said, is the promise of an oral arsenic for treatment of APL. ATRA is administered orally. “I think an all-oral regimen for APL is not far in the future,” he said.


Thursday, April 10, 2014

 

BY HEATHER LINDSEY

 

NEW YORK -- Cancer screening in transgender people may sometimes require a modified approach to current guidelines, according to researchers at a meeting here at Memorial Sloan Kettering Cancer Center focused on cancer in lesbian, gay, bisexual, and transgender (LGBT) communities. Transgender patients may also have to contend with obstacles to culturally competent cancer care, as indicated by survey results from the Cancer’s Margins project of the University of British Columbia.

 

Little Research Available

Only a limited body of research is available concerning the biomedical aspects of cancer care for transgender patients, said Evan Taylor, MSW, a doctoral student in the Centre for Cross-Faculty Inquiry in the Faculty of Education Program at the University of British Columbia and Research Assistant for Cancer’s Margins.

 

Although some case studies have pointed to an increased cancer risk from hormone treatments in transgender populations, this has not been definitively addressed in large trials, he noted. Case studies also recommend modifications to some routine cancer screenings, he said.

 

Another speaker, Ronica Mukerjee, FNP, Lac, MSN, MsA, NP, an acupuncturist at Collective Primary Care and former Director of Transgender Health for Community Healthcare Network in New York, said that because studies of transgender people are lacking, providers generally follow the screening guidelines published by organizations such as the U.S. Preventive Services Task Force (USPSTF) and the American Academy of Family Physicians and may make modifications based on extrapolated data -- for example, studies of postmenopausal women on hormone-replacement therapy.

 

Cancer Mortality Not Increased

Notably, a 2011 study (Eur J Endocrinol 2011;164:635-642) of 966 male-to-female (MTF) and 365 female-to-male (FTM) individuals, found that there is no increased cancer mortality in these populations, she said. However, the rates of lung cancer were significant higher, possibly due to heavier smoking in these individuals.

 

“You’ll see that trans patients smoke more than the LGB population,” she said. Consequently, health care providers should screen their transgender patients for past or present tobacco use. Poverty, stressful living, and lack of employment are often factors that transgender individuals are coping with and that contribute to the likelihood of smoking.

 

The rates of hematologic malignancies were also shown to be higher in the 2011 study, and researchers theorized that this might have been due to HIV-associated non-Hodgkin lymphoma.

 

Screening in FTM patients

Female-to-male transgender people need to receive gynecological pelvic and chest or breast care, Mukerjee continued. For cervical cancer screening in this population, health care providers should follow the guidelines of the American Society for Colposcopy and Cervical Pathology (ASCCP) for Pap smear.

 

“There’s no evidence that testosterone increases or reduces the risk of cervical cancer,” she said. If the patient is low risk based on HPV status, precancerous lesions are also unlikely to present. However, pathologists may find a higher prevalence of parabasal cells, which are associated with atrophy in postmenopausal women. If patients have undergone a hysterectomy, providers should find out if the cervix was kept. If it was, then a Pap smear needs to be performed.

 

Physicians and researchers often wonder about an elevated risk of endometrial and ovarian cancer in FTM patients, Mukerjee continued. “There’s a lot of unknowns in this area, but we do know that there’s no real evidence that taking testosterone leads to endometrial hyperplasia or proliferation.

 

“What we’ve seen in the small studies that are out there is that there is an atrophic effect of androgen on the endometrium, and PCOS [polycystic ovarian syndrome]-like changes are more prevalent with testosterone,” she said, citing J Sex Med 2009;6:3193-3200 as one example.

 

Overall, uterine histology is not very different in this population, except for the lack proliferation and menstruation, she said. Researchers can extrapolate that if there’s not a lot of cells growing, then there is less likelihood that someone is going to get a cancerous growth.

 

“There is, however, some weak evidence that PCOS may increase ovarian cancer, and with testosterone usage the risk of PCOS is greater,” she said. Additionally, transgender patients older than 40 and with a family history of the disease are also at elevated risk. In general, the USPSTF guidelines for ovarian cancer screening do not extend beyond performing a bimanual examination.

 

Some physicians may want to recommend a hysterectomy or an oophorectomy as prevention in FTM patients, Mukerjee said, adding that such a recommendation requires a comprehensive conversation with the patient about the procedure’s implications -- “Still, it might be something that the patient wants.”

 

For breast cancer screening, the USPSTF guidelines should be followed for natal sex, Mukerjee said. “For patients who have had chest surgery, there’s definitely mammary tissue that’s left, so doing a chest wall palpation is a good idea on a yearly basis.” Generally, a mammogram is not feasible, but sonogram or an MRI may be useful.

 

Mhel Kavanaugh-Lynch, MD, MPH, Director of the California Breast Cancer Research Program, said that although some health care providers suspect that long-term testosterone use may elevate breast cancer risk because the hormone may convert to estrogen, specific data in the transgender population are not available to support that theory.

 

Finally, FTM individuals who are HIV-positive and have an abnormal cervical Pap test or obvious condyloma should be screened for anal cancer with high-resolution anoscopy (HRA) to see if biopsy or removal is needed, said Mukerjee. 

 

Screening in MTF Patients

For MTF patients, “the big question is about prostate cancer screening,” Kavanaugh-Lynch said. There have been case reports of prostate cancer in MTF patients pre- and post-feminizing genital surgery.”

 

The androgen-blockers that MTF patients may be taking can suppress the growth of prostate cancer cells. However, because the therapy can also suppress prostate-specific antigen, PSA tests are no longer reliable in those who may have prostate cancer. Performing a digital rectal exam and educating all patients older than age 50 about prostate health is critical, she said.

 

The prostate is not removed with feminizing genital surgery, added Mukerjee. In patients with a neovagina, the prostate needs to be checked anterior to the vaginal wall. “It’s not going to be a rectal test anymore for the prostate,” she said.

 

Breast-screening mammography in MTF patients should occur every one to two years in those over age 50 with additional risk factors, including estrogen and progestin use for more than five years, a positive family history of breast cancer, and a body mass index of more than 35, she said. “Still, there are some people who, of course, say start screening at age 40.”

 

In MTF individuals the risk of breast cancer is going to be lower, Kavanaugh-Lynch said. However, long-term estrogen use in this population may elevate the risk of breast cancer. Few data are available on incidence, “but it happens and it happens with some frequency,” she said.

 

Additionally, in MTF patients, because breast implants may make detection more difficult, getting an appropriate mammogram is important, she said.

 

While breast cancer screening is necessary, Pap tests are not needed in MTF patients because a cervix is not created with vaginoplasty, Mukerjee said. The development of neovaginal condyloma is possible, which is notable because the neovagina is lined with keratinized tissue. However, condyloma are rarely associated with cancer, and overall, “there really have not been many case reports of neovaginal cancers.”

 

Finally, MTF patients should also be screened for anal cancer with anal Pap smears if patients are HIV positive, Mukerjee said.  

 

Contraindications for Hormonal Treatment

Transgender patients diagnosed with cancer may have to contend with contraindications to their hormone treatment. Testosterone, which can be converted to estrogen, and estrogen therapy are contraindicated in patients with estrogen receptor (ER) positive breast cancer, Mukerjee noted. These hormones may also need to be avoided in patients with ER-sensitive lung cancer, although more research is needed on this topic, she said.

 

Testosterone-blockers, especially spironolactone, should be avoided in patients with end-stage renal disease, which can come from cancerous causes, she noted.

 

Patients with transaminases levels three times the above upper limit of normal, which can occur with hepatic cancer, need to be closely monitored if they are receiving hormone therapy, Mukerjee noted. Finally, hormone therapy is contraindicated in patients with uterine cancer.  

 

Minority gender and minority sexuality remain irrevocably linked with health care decision-making and are associated with poorer health outcomes in cancer patients, Taylor said.

 

Missing from the research literature is information on transgender people’s actual lived experiences with cancer, which is part of what Cancer’s Margins is trying to address. Preliminary interview data from 62 participants across Canada who identified themselves as queer, gay, lesbian, bisexual, or transgender has offered many insights into the implications of gender and sexual marginality and the need for culturally competent cancer care, Taylor said.

 

For example, transgender health needs are not being addressed concurrently with cancer care. Oncologists may

simply tell the patient to stop taking hormone treatment without talking about transgender health.

 

Additionally, medical forms are often difficult to fill out due to the male or female delineation, and patients have to constantly negotiate when and where to educate their cancer health care providers about their gender.

 

Peer support can also be challenging to access for transgender patients, Taylor noted. Often, people running the support groups may not understand the meaning of transgender or gender identification and how it differs from sexual orientation -- gender is usually classified as two distinct sexes. She gave the example of one FTM survey participant with ovarian cancer who decided to access a support group, but felt he had hide his gender identity.

 

Survey responses also indicate that transgender patients’ cancer health care decisions are negatively affected by the lack of research data available and the absence of a cancer registry tracking by gender. As a result, information on hormone treatment and cancer risk is not readily available through their health care providers.

 

The Cancer’s Margins project has also found that the “intersectional complexities” of transgender cancer patients need to be considered, Taylor noted. “Transgender people’s cancer experiences are shaped by intersectional modes of privilege and oppression, such as gender, socioeconomic status, and racialization.”

 

Despite the many obstacles, though, she concluded, transgender patients are highly motivated to access cancer health care and transgender health and community support.

 


Sunday, April 06, 2014

BY ROBERT H. CARLSON

 

SAN DIEGO, Calif. -- The drug palbociclib (PD-0332991), an inhibitor of cyclin-dependent kinases (CDK) 4 and 6, significantly improved progression-free survival when administered as a first-line treatment along with the aromatase inhibitor letrozole, in patients with ER-positive HER2-negative metastatic breast cancer. These results from the Phase II PALOMA-1 study were presented here today at the American Association for Cancer Research Annual Meeting (Abstract CT101).

 

Median progression-free survival was 20.2 months for the 84 patients receiving the palbociclib-letrozole combination versus 10.2 months for 81 patients receiving letrozole alone, reported

Richard S. Finn, MD, Associate Professor of Medicine at UCLA.

 

The progression-free survival hazard ratio for women taking the combination was 0.49 compared with women receiving letrozole alone. Overall survival was trending in favor of palbociclib-letrozole, Finn said, but the difference was not statistically significant.

 

The study’s senior author is Dennis Slamon, MD, PHD, Professor of Medicine at UCLA and Director of the Revlon/UCLA Women’s Cancer Research Program, where the preclinical work was performed. The study was sponsored by Pfizer Oncology.

 

Cyclin-dependent kinases have been around for some time. The Nobel Prize in 2001 was awarded to scientists responsible for the discovery and identification of cyclin, CDKs, and cell cycle checkpoints – Leland H. Hartwell, PhD; Sir Tim Hunt, FRCS; and Sir Paul M. Nurse, PhD.

 

Palbociclib blocks the transition from G1 to S phase in the cell cycle where CDK-4 and-6 plays a critical role in regulating cell metabolism.

 

Finn said that palbociclib is unlike earlier CDK inhibitors which were “pan CDK inhibitors,” while this second-generation CDK-4/6 inhibitor is very specific in blocking CDK-4/6, leading to less toxicity.

 

PALOMA-1 comprised two parts, based on biomarkers: Part 1 included ER-positive patients; women in Part 2 also had ER-positive disease and their tumors also showed changes in cyclin D1 and/or loss of p16. This was intended to test whether or not biomarkers could further define appropriate candidates for treatment.

 

Patients in both parts were randomly assigned to receive letrozole at 2.5 mg daily continuously with or without palbociclib at 125 mg on a three-weeks-on/one-week-off treatment course. About one-third of patients had prior hormonal therapy and chemotherapy in the adjuvant setting.

 

ER-Negative Status Best Biomarker

Flinn said that ER-negative status was the best biomarker for selecting patients, and changes in cyclin D1 and/or loss of p16 were not as predictive.

 

But interestingly, while progression-free survival was superior for all patients on the combination arms, progression-free survival did differ by biomarker status.

 

Among patients in part 1 of the study, selected by ER-positive status, median progression-free survival was 26.1 months for the 34 patients taking palbociclib-letrozole versus 5.7 months for the 32 patients taking letrozole alone.

 

For those in part 2, selected by other biomarkers, compared with patients in part 1, median progression-free survival was less for 50 patients taking palbociclib-letrozole, at 18.1 months, but higher for the 40 patients taking letrozole alone, at 11.1 months.

 

Finn said he thought that might reflect how cyclin-D selection affects the response to letrozole.

 

The best overall response also favored palbociclib-letrozole, with a 43 percent objective response rate for the combination versus 33 percent for letrozole alone.

 

Overall Survival Data Not Mature

The outcome most anticipated for the trial was overall survival, and Finn did report a trend favoring palbociclib-letrozole:  Median overall survival was 37.5 months for palbociclib-letrozole versus 33.3 months for letrozole alone – but this was not a statistically significant difference.

 

“Survival events in ER-positive breast-cancer take time to evolve, but we are very encouraged by the overall survival,” Finn said. “This is a positive trend in the right direction -- we’re seeing a clear separation between the two arms and hopefully, this will be maintained over time.”

 

The most common toxicity with palbociclib was neutropenia: 20 percent of patients had grade 2, 48 percent had grade 3, and 6 percent had grade 4. For the letrozole-alone arms the rates of neutropenia by grade was four percent, one percent, and none, respectively.

 

But Finn said this was not the neutropenia seen with chemotherapy.

 

“This neutropenia is self-limited, patients recover easily, and most importantly, we do not see neutropenic fever.”

 

He said neutropenia is an on-target, anti-proliferative side effect of palbociclib and signifies inhibition of CDK4 and its effect on bone marrow.

 

Leukopenia, fatigue, and anemia were also more common in the combination arm of the study.

 

Treatment was discontinued by 50 percent (42/84) of the palbociclib-letrozole patients and 70 percent (57/81) of the letrozole-alone patients, due to progressive disease.

 

Palbociclib received Breakthrough Therapy designation from the Food and Drug Administration in April 2013  based on interim data from this trial (OT 5/10/13 issue).

 

Market analysts before the report speculated whether palbociclib would be a blockbuster drug for Pfizer. That remains to be seen, and will depend on how overall survival rates develop, how soon the drug is submitted for Food and Drug Administration approval, and whether it is approved.

 

Flinn commented in an interview after his presentation here that “for patients, it is looking like it is going to be a blockbuster. To double progression-free survival in this setting is unprecedented --there has never been an agent added to endocrine therapy that has had this degree of impact.”

 

Palbociclib is being tested in randomized, double-blind Phase III trials, in combination with letrozole (PALOMA-2) and fulvestrant (PALOMA-3) for patients with late-stage, metastatic breast cancers, and in combination with standard endocrine therapy (PENELOPE-B) for early-stage HER2-positive and HER2-negative breast cancers.

 

‘Results Positive, But Wait for Phase III Data’

The Discussant for the study, Jose Baselga, MD, PhD, Physician-in-Chief at Memorial Sloan Kettering Cancer Center, said that although overall survival data were not mature, “these results are strikingly positive, and with a large potential impact to patients with ER-positive breast cancer.”

 

Baselga did note that palbociclib still lacks a predictive biomarker that correlates with efficacy other than ER status. “Further work needs to be done here,” he said, suggesting that looking for the presence of nuclear D1 would be a good place to start.

 

He also pointed out that in this open label trial the primary endpoint -- progression-free survival -- was assessed by the investigators, which allows a potential for bias.

 

“But the elephant in the room is some negative results we have had with randomized Phase II studies,” Baselga said. “Many of you will remember the so-called PARP-inhibitor iniparib that showed very positive progression-free survival, and even an improvement in survival, and yet [publication of Phase II results] was followed by a totally negative Phase III study.”

 

Baselga also noted that the progression-free median survival of 10.2 months in the letrozole-alone control arm in PALOMA-1 was less than that seen in other recent aromatase inhibitors trials – specifically, the FIRST trial, with 13.1 months; and the SWOG S0226 trial, with 13.5 months.

 

He said he thought that the double-blind randomized Phase III PALOMA-2 study, now accruing patients, will eliminate some of these questions.

 

“It has been a long journey from the discovery of cyclin D and CDK-4 and -6 to today’s clinical results,” Baselga concluded. “The palbociclib results presented today are very positive, and if confirmed by the ongoing Phase III study, palbociclib in combination with hormonal therapy would be a new standard of care in the therapy of patients with advanced ER-positive disease.”