Skip Navigation LinksHome > Blogs > Online First/Online Only
Online First/Online Only
Articles/items published ahead of print or only online.
Saturday, August 29, 2015



Recent news headlines have suggested that women with the earliest form of breast cancer should rethink undergoing treatment because it may not impact their long-term survival. But breast cancer experts interviewed for this article say the study results that spurred those headlines should not be interpreted as a message to forego or change standard treatment.


In the observational study, available online ahead of print in JAMA Oncology, scientists at the Women’s College Research Institute in Toronto, analyzed data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results database, which included information on 108,196 women with ductal carcinoma in situ (DCIS) who were followed for 20 years.


DCIS is the presence of abnormal cells inside a milk duct in the breast, the earliest form of breast cancer, often called "Stage 0." The lead study author, Steven A. Narod, MD, Senior Scientist and Director of the Familial Breast Cancer Research Unit, explained in an interview that DCIS is usually discovered during a mammogram, and that three standard treatment courses are typically available: lumpectomy, lumpectomy with radiation, or mastectomy. Sometimes medication is also prescribed. All the women in the study had received some type of treatment, he said.


Narod is also Professor in the Dalla Lana School of Public Health and the Department of Medicine at the University of Toronto, as well as a Tier 1 Canada Research Chair in Breast Cancer.


The study showed that women who undergo DCIS treatment have a 3.3 percent risk of dying of breast cancer after two decades--almost twice that by women in the general population.


"The three treatments seemed equivalent," Narod said. “Most of the women who died of breast cancer had cancer that had spread by the time they were diagnosed with DCIS. The DCIS had probably already metastasized when it was diagnosed and local treatment wasn't sufficient."


 Jennifer Litton, MD, Associate Professor in the Department of Breast Medical Oncology at the University of Texas MD Anderson Cancer Center, said it’s an interesting paper but that even more interesting has been the media coverage: "I think some people may have interpreted the paper based on their own bias or agenda. But when you read the paper, this was a very well-done, retrospective study using the SEER database of women with DCIS who received therapy and their outcomes. It does not tell us what happened to women with a diagnosis of DCIS who did not receive treatment."


According to the American Cancer Society, 60,290 new cases of carcinoma in situ (CIS) will be diagnosed in the United States in 2015. The big debate raised in the recent news articles was: "Which, if any treatment should women with DCIS undergo to avoid recurrence?"


Litton, who was not involved with the study, clarifies: "The new study doesn't tell us at all that women with DCIS shouldn't get treatment."


What it does offer, she said, is more a frame of reference. "This study does give us lovely background and insight into potentially who are the groups we should target for clinical trials in order to look at other methods of surveillance. But at this point, it in no way suggests that there should be a change to the standard of care in any practice."


Litton said there's always been a lot of interest in looking at women who need less intervention, but that clinical trials to determine this approach are needed.


"Clinical trials are difficult to do, but before we can change the standard of care we're going to have to do that. This research is interesting and hypothesis-generating but it isn't the information that tells us who we should and should not take to treatment.”

 Don Dizon, MD, Clinical Co-director of Gynecologic Oncology at Massachusetts General Hospital Cancer Center, said, "The big message should not be lost: the vast majority of women diagnosed with DCIS survive." Dizon was also not involved with the new study.


"DCIS is not a normal finding in the breast. So, finding something abnormal on histology prompts providers and patients for an action – what are we going to do about it? So much of decision-making is collaboration between those diagnosed and those who treat. I think it’s wrong to suggest that doctors and surgeons are recommending treatment “aggressive” or “not so aggressive” in the absence of discussion," Dizon told OT.


He said patients would bring their own goals and preferences to treatment: "What we need to do more of, or at least a better job of, is making sure that knowledge is imparted – inform the discussion through education of patients and their families, including making distinctions about in situ versus invasive breast cancer, and then informing our own treatments with the reasons why we do what we do."


Dizon said that if anything, these data suggest that breast cancer specialists can be much more thoughtful in their approach to DCIS.


"It is not a one-size-fits-all approach. For example, we might recommend breast-conserving surgery and radiation therapy to younger women with DCIS. But maybe for older women over 65, we need only surgery to remove the lesion and not radiation."


He said it’s also important to look at DCIS as separate from invasive breast cancer – that these new long-term data show that women do well, better than can be expected, compared with women with invasive breast cancer.


Dizon also noted that because SEER data was used, "We do not know what treatment patterns, or even what the second cancers were, for those who developed invasive disease. Such data could inform the results, and we need to be cognizant of that."


 Laura Esserman, MD, MBA, Professor in the Departments of Surgery and Radiology and Director of the Carol Franc Buck Breast Care Center at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, wrote in an accompanying editorial that most of the women in the Narod et al study had lumpectomies and the rest had mastectomies. Some of the patients, she noted, were at higher risk, including younger patients under the age of 40, black women, and those with questionable molecular markers.


"The majority of DCIS is detected in women undergoing screening and who are recalled for biopsy of calcifications,” Esserman wrote. “To minimize the risk of overdiagnosis and/or overtreatment, it is time to reassess whether clustered amorphous calcifications should be a target for screening, recall, and biopsy, especially in older women.”


Esserman concluded by noting four points on what the sum total of the data on DCIS now suggests:

  • DCIS should be considered a “risk factor” for invasive breast cancer and an opportunity for targeted prevention;
  • Radiation therapy should not be routinely offered after lumpectomy for DCIS lesions that are not high risk;
  • Low- and intermediate-grade DCIS does not need to be a target for screening or early detection; and
  • Breast cancer specialists should continue to better understand the biological characteristics of the highest-risk DCIS cases and test targeted approaches to reduce death from breast cancer.

 Deanna Attai, MD, President of the American Society of Breast Surgeons and Assistant Clinical Professor in the Department of Surgery at UCLA David Geffen School of Medicine, who also spoke with OT, said the study generated so much interest among colleagues and the broader breast cancer community that she addressed it on her blog.


She told OT: "DCIS is not one disease. With each study that comes out, we get more and more evidence we're dealing with multiple diseases. Because we're dealing with multiple diseases, in a sense we need multiple treatment approaches--not a one size fits all.


“Look at the patient's age, tumor grade, extent of disease, along with a patient’s preferences and whether they understand these are our standard treatments but we're not sure about the long-term value of them in terms of improving survival. Couple that with understanding and recognizing that we don't have the ability to predict which patients will do well with less treatment."


Attai, a co-moderator of the weekly Breast Cancer Social Media tweetchat (#BCSM), also said physicians need to have open discussions with their patients regarding the differences between DCIS subtypes, and that patients and doctors themselves need to recognize their limitations.


"We need to acknowledge that we do not always have the right answers, inform the patient that decisions do not need to be made quickly, discuss cases in a multidisciplinary forum, and encourage second opinions. I think that is the ideal way to approach a patient with DCIS, and invasive cancer, as well."

Saturday, August 29, 2015



BARCELONA, Spain--The title of his presentation was “When Not to Operate in Rectal Cancer,” which the speaker admitted was an unusual topic for a surgeon to address.

But the focus was on organ preservation, and Geerard L. Beets, MD, of the Department of Surgical Oncology at the Netherlands Cancer Institute, speaking here at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer, explained why a watch-and-wait approach after neoadjuvant therapy is becoming more common.


Patient desire to avoid a colostomy is a factor, but perhaps most important: For non-metastatic rectal cancer after neoadjuvant therapy, overall survival appears to be the same for surgery and for watch-and-wait.


A study published in 2004 “shook the surgical world,” Beets said, as it showed an overall survival rate of 100 percent at five years for patients with stage 0 distal rectal cancer in an observation group following neoadjuvant therapy, compared with 88 percent in patients who had undergone resection (Ann Surg 2004;240:711-717).


Beets said four concepts are changing rectal surgery today:

·    A balance is necessary between survival and function;

·    Treatment can be adapted according to response to therapy;

·    Surgery and radiotherapy are complementary; and

·    Patience is of the essence: “Take your time before surgery for appropriate patients.”


“In the past 20 years we have obtained better survival and recurrence rates in rectal cancer by adding surgery and radiotherapy, but we may have forgotten a little bit about function, so now we are trying to get a balance--a better function without losing what we have gained in the last 20 years,” Beets said.


The concept of organ preservation does not follow technical developments as much as a change in the minds of surgeons and clinicians: “We are willing to let function be a part of the decision process.”


‘This is Something We Have to Get Used to’

Moving radiotherapy and chemotherapy upfront gives clinicians a lot of time to change a treatment plan, he said, “and this is something we have to get used to.”


In the past, the association between surgery and radiotherapy was not complementary, he explained. “The attitude was that we were targeting the same tumor so 'why try to kill it twice, why irradiate the primary tumor and then take it out. But now we'd rather think of this as two complementary strategies--when radiotherapy is good, maybe we can omit the surgery; if surgery is very good maybe we can omit the radiotherapy, and in some patients, we need both.


“And we are learning there is no rush--if you see a good response take your time,” he said. “Deferral of surgery has been demonstrated in anal cancer, so why not do that in rectal cancer?”


Watch-and-Wait Was Better

Beets reviewed the study that “shook the surgical world”--a trial of 265 patients with distal rectal adenocarcinoma considered resectable. All the patients were treated with neoadjuvant Chemoradiation—fluorouracil and leucovorin, and 5,040 cGy of radiotherapy.


Patients with an incomplete clinical response were referred to have radical surgical resection; those whose surgery resulted in pathologic stage 0 were compared with patients who had a complete clinical response after non-operative treatment. Five-year overall survival was 100 percent in the non-operative observation group following neoadjuvant therapy versus 88 percent in the surgical patients.


Disease-free survival rates were also superior in the observation group—92 percent--versus 83 percent in the resection group.


A 10-year update published last year (Int J Rad Oncol 2014;88:822-828) showed that local recurrence developed in 31 percent of patients who had initial clinical complete response (when regrowths of 12 months or less were grouped with late recurrences). No metastases originated from regrowth.


More than half of those recurrences developed within 12 months, and salvage therapy was possible in at least 90 percent of the recurrences, leading to a local disease control rate of 94 percent and an organ preservation rate of 78 percent.


“The estimate of patients potentially 'harmed' by watch-and-wait was estimated at two to three percent, but that is the mortality of any major procedure,” Beets said.


Putting Data into Practice

Beets said his institution has changed its protocol since 2004 for locally advanced pancreas cancer following chemoradiotherapy.


“After 10 weeks if it looks like there is residual tumor, then we do a total mesorectal excision [TME],” he said. “But if there is a complete response, we wait; and if it is a near complete response, we do a local excision, or we wait even longer.”


Selection is usually by digital rectal exam and endoscopy.


“Most importantly, you share with the patient the uncertainty that everything is gone and that there are risks and benefits, and if the patient is willing to accept this, they can enter the protocol,” Beets said. “You tell the patient there is a risk for local regrowth and that we need to do rigorous follow-up.”


The follow-up includes MRI and endoscopy every three months for the first year and then every six months.


Beets said his institution is now following 121 patients treated for rectal cancer, 106 of whom opted for watch-and-wait and 15 who received total mesorectal excision. Their mean age was 63, two-thirds of patients were in stage III, and three-quarters had distal tumors.


The overall survival rate at 2.5 years for the watch-and-wait group is 97 percent, and 100 percent among the total mesorectal excision group. “The good survival is not because we did not operate; this is just a biological selection of favorable patients,” he said.


Lessons Learned

Beets listed what he and colleagues have learned during this 10-year period:

·    They now wait 10 to 12 weeks for the reassessment after chemoradiotherapy;

·     Primary assessment tools are digital rectal exam and endoscopy, and less of MRI;

·     Assessment has become “a little more relaxed,” and near responders are accepted for watch-and-wait;

·    “The test of time” is considered a diagnostic tool;

·    There is less reliance on biopsies unless there is a clear regrowth;

·     Transanal endoscopic microsurgery (TEM) could increase the number of organ preservations in smaller tumors, “but in big tumors with a residual lesion, I am not sure TEM will be very helpful”; and

·    Clinicians are noticing a high interest by patients in organ preservation.


While organ preservation is feasible, it is not yet standard practice, Beets noted. “In intermediate/advanced tumors, where we have already decided to give upfront neoadjuvant therapy, you see a response rate of only 15 to 20 percent, but it is worth looking for a response.”


The largest group of patients who could benefit from organ preservation are those with smaller tumors. “About 50 percent of those tumors respond to adjuvant chemotherapy. With good selection and follow-up, the local regrowth rate is 10 to 15 percent, and salvage is possible with early detection of regrowth,” Beets said.


“My feeling is that there is little or no influence of watch-and-wait on survival, but that is a question mark until we have more evidence.”

Friday, August 28, 2015

New research has identified a novel nutrient-uptake process that maintains the activity of murine chronic myelogenous leukemia (CML) stem cells. The study in Nature Communications by a team of Japanese and Korean researchers found that certain nutrients support CML stem cell activity in vivo, thus suggesting a potential target for therapy.


“Although tyrosine kinase inhibitors [TKIs] such as the first-generation TKI imatinib mesylate and the second-generation TKIs dasatinib and nilotinib have markedly improved the prognosis of patients with chronic-phase CML, a cure remains elusive. To completely eradicate CML stem cells and CML, TKIs may have to be coupled with novel therapeutics targeting alternative mechanisms," the lead researcher, Kazuhito Naka, PhD, Associate Professor at Hiroshima University, explained in a news release.


CML stem cells were found to accumulate significantly higher levels of certain dipeptide species than normal hematopoietic stem cells do. As noted in the news release, once internalized, these dipeptide species act as nutrients for the CML stem cells and play a role in the maintenance of CML stem cells. Importantly, an inhibitor of the dipeptide uptake blocks CML stem cell activity in mice.


"Our proposed approach of using inhibitors to shut down a key nutrient-uptake process specific to CML stem cells, in combination with TKI therapy, may thus provide concrete therapeutic benefits to patients with CML,” Naka said. “It will open up a novel avenue for curative CML therapy.


“To our knowledge, our study is the first to demonstrate that CML stem cell activity depends on nutrient signaling that regulates post-translational phosphorylation of Smad3 at Ser208. Furthermore, we have shown that dipeptide-induced p38MAPK activation is responsible for this Smad3–Ser208 phosphorylation, and that Foxo3a binds specifically to Smad3 in LT-CML stem cells.”


The research also showed that the antibiotic cefadroxil attenuates dipeptide uptake by CML stem cells and so may be an option to use in combination with TKIs.


“However, we still do not understand how dipeptides act as a nutrient source for specific cell types, or how systemic dipeptide distribution contributes to normal health,” the team wrote in their conclusion. “Indeed, administration of cefadroxil in the absence of a TKI appeared to accelerate disease development in CML-affected mice… .Our proposed approach of using cefadroxil to shut down a key nutrient source specific to CML stem cells, in combination with TKI therapy, may thus bring concrete therapeutic benefits to CML patients.”

Thursday, August 27, 2015




BARCELONA, Spain--A mycobacterial product that stimulates the immune system and a drug that enzymatically depletes hyaluronan were highlighted here in presentations on new directions in pancreatic cancer at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer.


The Phase II trial in patients with tumors high in hyaluronan, the high-molecular-mass polysaccharide found in the extracellular matrix, showed improved response rates and progression-free survival when the anti-hyaluronan agent PEGPH20 was added to gemcitabine/nab-paclitaxel.


And the first positive study of an immunotherapy/chemotherapy combination in first-line treatment of pancreatic ductal cancer showed clinically meaningful extension of overall and progression-free survival with IMM-101, a mycobacterial product, combined with gemcitabine.


Tumors Rich in Hyaluronan

“Pancreas cancer is notorious for its desmoplastic stroma and fibro-inflammatory action, and hyaluronan is a major component of desmoplastic stroma--a barrier to therapeutic access,” explained Andrew E. Hendifar, MD, Medical Oncology Lead Investigator in the  Gastrointestinal Disease Research Group of Samuel Oschin Comprehensive Cancer Center of  Cedars Sinai Medical Center in Los Angeles.


Hyaluronan, a highly hydrophilic glycosaminoglycan, can generate a large immobile fluid phase, thus compromising access to the tumor by increasing tumor interstitial fluid pressure, compressing the vasculature, and producing a cell “coat,” he noted. Hyaluronan also signals through receptors on the cell surface.


Pancreas, breast, colon, and prostate cancers have been shown to accumulate high levels of hyaluronan.


Hendifar is lead author of the randomized Phase II HALO-109-202 trial, also known as Study 202, which is investigating the use of PEGPH20 plus nab-paclitaxel plus gemcitabine compared with nab-paclitaxel plus gemcitabine alone in patients with stage IV untreated pancreatic cancer. PEGYPH20 is pegylated recombinant human hyaluronidase, an enzyme that depletes hyaluronan.


In his report on the interim results on the first 146 patients in the study, he noted that PEGPH20 rapidly and sustainably decreases the content of hyaluronan in the tumor, thus inducing re-expansion of blood vessels and increasing intratumoral delivery of chemotherapy.


Patients with high hyaluronan-expressing cancer in this trial saw a statistically significant improvement in the objective response rate with the three-drug combination versus the chemotherapy-alone arm (52% vs. 24%). In contrast, patients with low hyaluronan content did not appear to benefit from PEGPH20, with objective response rates that were similar for both treatments: 37 and 38 percent, respectively.


Progression-free survival doubled in high-hyaluronan patients: 9.2 months with PEGPG20-gemcitabine/nab-paclitaxel versus 4.3 months with gemcitabine/nab-paclitaxel. And the median duration of response was 8.1 months with PEGPH20 versus 3.7 months for  gemcitabine/nab-paclitaxel. There was also a trend toward improved overall survival: 12 versus nine months.


The study was halted for a while after the first 146 patients were enrolled due to an imbalance in thromboembolic events in the PEGPH20 group, but enoxaparin was then added for prophylaxis and the study resumed. Hendifar said the trans-ischemic events were manageable in subsequent patients, with enoxaparin given at a dose of 1 mg/kg/day.


He noted that a global Phase III, randomized, double-blind, placebo-controlled trial comparing the same drugs in this patient population is scheduled to start in the first quarter of 2016.


Discussant: Hyaluronan Localized in Stroma

“We are seeing quite interesting results in progression-free survival with PEGPG20--nine versus four months, roughly, which was significant, but we see only a trend in improved overall survival,” said the Discussant for this session, Volker Heinemann, MD, PhD, Director of the Comprehensive Cancer Center of Ludwig-Maximilians-University in Germany.


“It is important to understand that hyaluronan is glycine that is over-expressed in pancreatic cancer and localized to the stroma,” he said, citing GUT 2013;62-112-120. “If you combine hyaluronidase with gemcitabine you can decrease proliferation, and you can decrease the tumor volume and have a positive effect on overall survival in the mouse model.”


Heinemann noted that the agent was tolerated quite well.


He added that the overall 24 percent response rate in the Study 202 control arm of gemcitabine-nab-paclitaxel is highly consistent with the 23 percent for the gemcitabine-nab-paclitaxel arm in the study reported by Von Hoff et al: NEJM 2013;369:1691-1703.


Progression-free survival rates were also similar in those two studies– 4.3 months in Study 202 and 5.5 months in the nab-paclitaxel study--as was overall survival (nine months and 8.5 months). “Of course, the control arm in Study 202 is just 21 patients compared with 431 in the Von Hoff study, so this comparison is to be used in brackets,” Heinemann added.


“But if we look at least at the consistency of the data by themselves, I think we can also appreciate that these response data with regard to objective response give us an overall survival picture that is quite impressive so far.”


IMAGE Trial Tests Mycobacterial Product

In the other highlighted pancreatic cancer study, the first positive evaluation of an immunotherapy/chemotherapy combination in first-line treatment of pancreatic ductal cancer showed clinically meaningful extension of overall and progression-free survival.


The randomized, open-label Phase II IMAGE (Immune Modulation and Gemcitabine Evaluation) trial combined IMM-101, a mycobacterial product, with gemcitabine (at 1,000 mg/m2) and compared that combination with gemcitabine alone in 110 patients.


Interestingly, the greatest improvements were seen in patients with metastatic disease, said the lead investigator, Angus G. Dalgleish, MD, Professor of Oncology in the Division of Clinical Sciences at St. George's University of London, U.K.


He explained that IMM-101 is a heat-killed mycobacterial product that stimulates innate and adaptive immune response. It is administered intradermally rather than subcutaneously, induces CD8+ cell responses, and reduces metastasis in mouse models.


“In this trial it significantly increased overall survival and progression-free survival, with no incremental toxicity or immune-related toxicities, while maintaining quality of life.” And although not statistically significant, there were improvements in neutropenia and fatigue that are very important in quality of life, he added.


The survival curve shape is very characteristic of immunotherapy, Dalgleish noted.


Study Specifics

There were 74 patients in the treated arm and 35 controls, all with inoperable pancreatic cancer and WHO performance status of zero to two. Two-thirds of the patients were age 65 or older, and the patients were treated at 20 sites in Europe.


Dalgleish reported median overall survival for all IMM-101-treated patients to be 6.7 versus 5.6 months for controls, a 20 percent increase, whereas median overall survival for metastatic patients was 7.0 months with IMM-101 versus 4.4 months for controls, a 59 percent increase.


Median progression-free survival with IMM-101 was also longer in metastatic patients: For all patients the progression-free survival was 4.1 months for the IMM-101 arm versus 2.4 months for controls--a 71 percent increase--whereas for metastatic patients it was 4.4 months versus 2.3 months--a 91 percent increase.


“Further investigation of IMM-101 with additional immunotherapies such as checkpoint inhibitors is logical,” Dalgleish concluded.


Discussant: Focus Changing from Stroma

In his discussion of the two trials, Heinemann said research in pancreatic cancer has for some time focused on peritumoral tissue and stroma. “We had understood pancreatic cancer as a tumor that is hypervascular and hyperperfused, and rich in collagen and in inflammatory reactions. The thought was that by reducing the stromal compartment we would improve the vascularity of the tumor, we would be able to deliver chemotherapy to a greater extent, and thereby improve antitumor efficacy.”


This seemed to be born out, he said, with the study by Von Hoff and co-workers of nab-paclitaxel plus gemcitabine versus gemcitabine alone. “At that time, the hypothesis was that nab-paclitaxel was focusing on peritumoral fibroblasts and would eliminate these tumors, and so the combination of gemcitabine plus nab-paclitaxel led to a stromal depletion,” Heinemann explained.


Those authors concluded that this was most likely the cause of an increase in gemcitabine accumulation in tumor cells, a response seen in other trials involving various tumors.


“Now I think all of us were quite shocked to see research--Cancer Cell 2014;25:719-734, Cancer Cell 2014;25:735-747--demonstrating that stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma,” Heinemann said. “In fact, stromal elements induced a decrease in fibroblasts, but on the other hand also caused evolution of undifferentiated pancreatic ductal carcinoma cells.


“This was in contrast to what we had expected, but it was supported by the fact that the INFINITY trial, using the sonic hedgehog (SHH) inhibitor IPI-926, in fact made the tumors more aggressive.”


He said this was supported by later works showing that stromal depletion was associated with shorter survival in mouse models--“We have come a long way in treating pancreatic cancer, from gemcitabine, to targeted therapy, to intensified chemotherapy, and now to stroma- and immune directed therapy.”

Tuesday, August 25, 2015



Researchers have for the first time shown that older patients with certain types of non-Hodgkin lymphoma (NHL) treated with fludarabine-containing chemotherapy (with or without rituximab), or those diagnosed with T-cell–activating autoimmune conditions, have an increased risk of developing cutaneous melanoma. The findings from this large-scale, population-based study, now online ahead of print in the Journal of Clinical Oncology (doi: 10.1200/JCO.2014.60.2094), thus identify high-risk survivors of NHL who would benefit most from regular full skin examinations to maximize opportunities for early detection of cutaneous melanoma.

The study’s lead author, Clara J.K. Lam, PhD, of the National Cancer Institute’s Radiation Epidemiology Branch, noted in an interview that although treatment advances have substantially improved the prognosis for NHL patients, secondary malignancies remain an important cause of morbidity and mortality among the approximately 700,000 survivors of NHL in the United States. Compared with the general population, survivors of NHL have an increased risk of developing melanoma, with particularly elevated risks among survivors of more indolent NHLs, specifically the type known as chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).


“We know that survivors of NHL have an increased risk of developing melanoma, but the reasons for this increased risk were not well understood. Our study linked two large databases--Surveillance, Epidemiology, and End Results (SEER)-Medicare and Medicare claims--to identify risk factors for developing melanoma among survivors of NHL, and we found that survivors of CLL/SLL who were treated with the fludarabine had an approximately two-fold increased risk of developing melanoma compared with survivors who did not receive that treatment.


“In addition, the results showed that survivors of CLL/SLL who had a history of certain autoimmune conditions also had about a two-fold increased risk of developing melanoma, compared with those who didn't have those autoimmune conditions.”


44,870 Survivors

Lam and her colleagues evaluated second melanoma risk among 44,870 one-year survivors of first primary NHL who were diagnosed at age 66 to 83 from 1992 to 2009. A total of 202 second melanoma cases occurred among survivors of NHL, including 91 after CLL/SLL and 111 after other NHL subtypes.


Melanoma risk after CLL/SLL was significantly increased among patients who received infused fludarabine-containing chemotherapy with or without rituximab. Significantly elevated risks also were associated with T-cell activating autoimmune diseases diagnosed before CLL/SLL or after CLL/SLL.


In contrast, among patients with other NHL subtypes, melanoma risk was not associated with specific treatments or with T-cell/B-cell immune conditions.


Mechanism Unclear

“Although our data supported the role for immune dysfunction, and T-cell dysfunction in particular, in the development of melanoma after CLL/SLL, the exact mechanism remains unknown,” Lam said. “Further research will be needed to characterize the specific immune system abnormalities that impact melanoma.”


In general, most infections did not seem to be related to melanoma risks, except for urinary tract infections (in CLL/SLL patients), localized scleroderma, pneumonia, and gastrohepatic infections (all in patients with other NHLs).


The researchers noted that CLL/SLL patients experience “profound, prolonged” immune dysfunction characterized by defective B-cell and T-cell function. This contributes to an increased incidence of infections and autoimmune diseases.


Previous studies have shown an increase in the risk of second cancers, particularly skin cancers, as well as treatment-related acute myeloid leukemia and solid malignancies in fludarabine-treated patients with CLL/SLL. But this is the first study to directly compare the melanoma risks in patients treated with and without fludarabine.


More Advanced, More Aggressive

Melanomas occurring after CLL/SLL were more likely to be at least one millimeter thick compared with those occurring after other NHLs—“which is consistent with previous studies reporting these melanomas to be more advanced and more aggressive than melanomas that arise in the general population,” Lam and her colleagues wrote.


The clinical success of immunotherapy directed at T-cell checkpoints in treating metastatic melanoma shows the importance of T cells in the antitumor response in patients with melanoma, they added.


Possible Limitations

Regarding the study’s limitations, the team added that there were no data on the dose and duration of chemotherapy, and information on oral chemotherapy agents, including chlorambucil or other oral alkylators, was not available for the duration of follow-up. In addition, because of the nature of the Medicare claims database, some exposures may have been misclassified, Lam said. Also, patients younger than 65 at NHL diagnosis were not included, so the findings may not be generalizable to younger populations.


In summary, she said: “NHL survivors who are 65 years and older, especially those treated with fludarabine and/or who have autoimmune diseases, may benefit from regular full body skin examinations to maximize opportunities for early detection of melanoma. Hematologists/oncologists and physicians involved in long-term follow-up care for these patients should be aware of the risks of second malignancies in those treated with fludarabine chemotherapy.”


‘Clearly at Increased Risk’

Asked for his perspective for this article, Jeffrey M. Weinberg, MD, Associate Clinical Professor of Dermatology at Mount Sinai School of Medicine in New York, said: “These older NHL patients are clearly at increased risk of melanoma. Oncologists can help prevent the development of melanoma in their NHL patients by arranging frequent all-body skin exams with dermatologists, and by suggesting that their patients perform self-exams monthly. Oncologists should connect with their local dermatologists to work collaboratively on this issue.”