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A father and a son

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Anas Younes_father and son.JPGOncologists thrive on prolonging life and decreasing human suffering. They have to be optimistic, without providing false hope. They also have to be honest when all treatments fail and clearly communicate a poor prognosis to patients and their families. Most of the time, the patient's overall medical condition and tumor status easily guide decisions to treat or not to treat. But sometimes even the most skilled oncologists find it difficult to predict the future. In these situations, decisions are made through candid discussions with the patient and the caregivers. The patient's final decision to request more therapy or to focus on comfort care is usually based not only on the medical status, but also on social and economic factors. Some patients also take into account the possible burden they may impose on their caregivers.

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The patient was admitted to the hospital with rapidly progressing lymphoma. His lymphoma already relapsed before. As I visited him, I planned to discuss the prognosis and help him decide whether he wanted to try more therapy. 

Younes_hospitalrounds.JPGIn the opening line of his famous book "Anna Karenina," Tolstoy wrote, "All happy families are alike; each unhappy family is unhappy in its own way." To paraphrase him, I have also observed that each family deals with cancer in its own way.

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Doctors, especially oncologists, learn how to keep an emotional distance from their patients. By doing so, they can make critical decisions with objectivity and avoid early burnout. This approach is frequently, and incorrectly, viewed by patients and their families as a sign of lack of empathy.   

During hospital rounds, doctors need to carefully regulate empathy and continuously adjust their own emotions to properly respond to patients' fear, happiness, pain, anger, sadness and hope, without losing focus on resolving complicated medical problems.  

While doing so, doctors also have the opportunity to observe the lives of others during their most vulnerable moments. Some of these "snap shots"  can be  profound in reminding us of the basics of our humanity.

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After six years of fighting cancer, the patient progressively developed multi-organ failure, generalized swelling, shortness of breath and pain. He had already received ten  treatment regimens, including stem cell transplant and experimental therapies. While his body was getting weaker, his tumor was getting stronger. He was admitted to my service, where I met him and his wife for the first time. He was in his mid-sixties. He was tired, breathing heavily and somewhat drowsy from the pain medicine that he was given. His wife also looked tired from the long days and hours she spent caring for him. Deep inside, she knew that they had lost the battle. She wanted him to die in the comfort of their home. She asked for help with arrangements for home hospice care.

brontoyounes.jpgThis year, approximately 11,000 patients combined will be diagnosed with Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL). Compared to other cancers, such as breast and lung, these two lymphomas are considered relatively rare cancers. So, chances are, you didn't hear the news about brentuximab vedotin (SGN-35), which is now called Adcetris.  

HL and ALCL are potentially highly curable types of lymphoma when conventional chemotherapy regimens and radiation therapy are used. For this reason, no new drugs have been approved by the U.S. Food and Drug Administration for Hodgkin lymphoma since 1977.

But if you are one of the unlucky ones who aren't cured with these conventional regimens, today is a good day for you. Indeed, it's a good day for all of us. A good day for humanity.

A new drug has been approved

Today, the Oncologic Drugs Advisory Committee/ODAC, an FDA advisory panel, voted 10-0 to recommend accelerated approval for Adcetris to treat patients with relapsed Hodgkin lymphoma after having a stem cell transplant, and for patients with relapsed or resistant systemic ALCL.
 

Of the approximately 76,000 new patients who will be diagnosed with non-Hodgkin lymphoma (NHL) this year, 15% will have peripheral T-cell lymphoma (PTCL).

The World Health Organization (WHO) lists 21 major subtypes of mature PTCL. Therefore, because of the relatively rare heterogeneity of the disease, PTCL is more challenging than other types of NHL from diagnostic and therapeutic points of view.

To meet these challenges, we've assembled a world-class team of medical oncologists, dermatologists, radiation therapists, hematopathologists and stem cell transplant experts to create a multidisciplinary T-cell lymphoma working group. During the monthly meeting of our group, which I chair, we discuss challenging cases and recent clinical and pre-clinical data in PTCL, in addition to new concepts to design and conduct innovative clinical trials for PTCL patients.

Our mission is to improve the cure rate of patients with PTCL and reduce treatment-related toxicity by developing novel targeted therapy using rationally designed small molecules, antibodies and combination regimens of biologic agents.




younesJune11.jpgUp until now, the role of intensified therapy for newly diagnosed lymphoma in the rituximab era remained unknown. 

This week at ASCO, four independent randomized trials, looking at different strategies, reported that more intensive front-line therapy offers no added advantage over standard chemotherapy regimens in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). 

If you don't have the time to read this full report, all you need to know is that RCHOP-21 remains the standard of care.

Last night, millions of people around the world were glued to their TVs watching the successful rescue of the miners in Chile, who were trapped in a small chamber about 2,300 feet below the surface.

miners.jpgFor 17 days after the accident on Aug. 5, we didn't know their fate, and the whole world became skeptical that any of the miners would survive. But when we learned that they were still alive, all of us became hopeful that there was a chance to bring them back to the surface, alive.   

Although no one really knows these men, no one can recall their names and it is highly unlikely that we will ever meet them in person, last night we all cheered when the first man emerged from the small capsule back into the real world. We watched and cheered because this drama represented human triumph after months of unprecedented endurance.

The first thing that came to my mind as I watched is how many similarities this experience has with what cancer patients go through. Many patients and their families face a long period of uncertainty while getting their "rescue" version of anti-cancer therapy. We do not have precise measurements to predict who is going to be cured and who is not. Patients frequently have to wait until the end of therapy and many years later to learn whether they are cured.  
Similarly, the miners, their families and the entire world had numerous doubts about their final results. But the tremendous support from their families, friends and the public gave them a great sense of optimism, so they never lost hope. Recent studies showed that cancer patients who have social support also fare better.

Second, these men had to endure living underground in unprecedented conditions for more than two months before they were rescued. It took time, consultations, excellent planning, a team effort and patience to save their lives. There was no magic bullet.

What was amazing is that the miners and families understood that, and remained calm and collected throughout the lengthy ordeal. Taking shortcuts and reacting under pressure could have resulted in a different outcome.

But the last and most striking observation was how that these miners decided to surface back into our world.  They all shaved, took showers and put on clean clothes. They wanted to get back as soon as possible to their normal lives. Anyone would have understood, and perhaps would have been more sympathetic, if these men surfaced with shaggy long beards and dirty clothes. But after living that long with anxiety, uncertainty and fear, they elected to return to their normal lives rather than gain sympathy. That is a tremendous state of mind, and anyone should admire that. 

Younes.jpgOver the years, I have met and taken care of so many patients who came from different walks of life, different ages, tumor status and had various toxic treatments. I always admired those who took the time and made the effort, despite this most stressful period in their lives, to present themselves to their families, caregivers and the surrounding world in their best "normal" way, keeping a sense of optimism and courage. Somehow, I always felt that those patients did better. So did these miners.


Younes MD Aug 2010A year ago this month I launched this medical Facebook page.

It feels like yesterday.

This idea came four months after I started to use Twitter (http://twitter.com/dranasyounes) to share important information on medicine and cancer. Initially, the page allowed followers to be "friends." After consultation with colleagues, MD Anderson Communications Office staff and some of my followers, the site was changed to allow "fans" to follow me rather than friends. This allowed my followers, some of whom are patients of mine, to keep their privacy while giving them the opportunity to read and comment on my posts.

Since then, I have posted 633 links to important medical articles published in scientific and lay media outlets, an average of two posts every day. To date, this page has 617 followers, 81% of whom are women, and 51% are younger than age 45. Four hundred and eighty-nine of my followers are from the United States and 145 live in Houston.

Likewise, to date I have 1,511 followers on Twitter, and I tweet an average of seven links each day, mainly covering cancer (especially lymphoma) and other medical topics.

Thanks to support from the MD Anderson Communications Office, I have blogged 12 times here in Cancerwise, including blogging from the past two American Society of Clinical Oncology meetings In between, four short videos (http://bit.ly/cwsQZz, http://bit.ly/b51d8U, http://bit.ly/9Bl71b, http://bit.ly/bVFbqY) and two iTunes webcasts were also posted to promote clinical trials on lymphoma.

As I stated in previous blogs, this effort not only provides credible educational sources of information to the general public, but also has been a successful tool to promote participation in innovative clinical trials at our center. With time, I communicated with patients and their families, doctors, scientists and curious minds, most of whom I have never met in person.

Making myself available through social media and posting my e-mail address on my Facebook page allowed many people around the world to ask questions. In many cases, this resulted in referrals of patients who are interested in participating in clinical trials. Every week I get e-mails from patients and families around the world asking for help. This is a lot of work for me, but I consider it a good public service.

My goal is to reach out to every patient with lymphoma. Over the past year, 617 individuals followed my Facebook page and, of course, not all of them are lymphoma patients. This year, it is expected that 74,000 new patients will be diagnosed with lymphoma (both Hodgkin and non-Hodgkin) in the United States. That means I will have to reach out to 73,400 more individuals!

If you don't know me, I would like to assure you that I think this goal is achievable. I just have to keep working on it. But I would also like you to help me achieve this goal.


twitter_icon_15.jpgFollow Dr. Younes on Twitter


facebook_icon_15.jpgDr Younes on Facebook

Two new targeted agents, panobinostat and PCI32765, were presented at ASCO and demonstrated promising clinical activity for the treatment of non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL).

In one study, A. Surrreda presented results from an ongoing large Phase II study of the oral pan histone deacetylase inhibitor (HDACi) in patients with relapsed HL. Remarkably, despite the relative rarity of the patient population, this international trial has completed enrollment with 129 patients at 45 sites in 13 countries.

Younes_August.jpg

Oral panobinostat was administered at a dose of 40 mg three times per week, every week, in 21-day cycles. Dose delays and reductions were allowed for management of toxicity. Patients had a median age of 32 years, with a median prior treatment regimens of four. Importantly, 37% had no response on last therapy and 80% had a prior autologous stem cell transplant. 

Based on objective response assessment, 17 patients achieved major responses and 71% of the patients had tumor reductions. Common grade 1 and 2 toxicity included nausea, vomiting, and diarrhea. The most common grade 3 and 4 toxicity were thrombocytopenia and anemia. Thus, this study confirms the clinical activity of HDACi in HL.

However, this study is the largest single agent Phase II study to be conducted in patients with relapsed HL, after receiving ASCT, which represents a population of unmet medical need. The final analysis of this study is expected to be available by the end of this year.

While the single agent activity looks very promising, panobinostat-based combination clinical trials are currently enrolling patients with relapsed HL. One interesting study is a combination of everolimus plus panobinostat, which is currently enrolling patients at MD Anderson.

In a second study, N. Fowler presented very exciting data from an ongoing Phase I study using the oral Bruton's tyrosine Kinase (Btk) inhibitor PCI32765 in patients with relapsed B cell lymphoma. Btk is an important component of B-cell receptor signaling pathway, downstream of Syk.

The first study to target this activated pathway was recently published using the oral Syk inhibitor fostamatinib, which demonstrated promising clinical activity in a variety of B-cell lymphoma, especially chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Based on promising preclinical data in B-cell NHL, a study was conducted to test the safety, pharmacokinetics, pharmaco-dynamics, and efficacy of PCI-32765, a potent, selective oral inhibitor of Btk.

At the time of the report, 47 patients were enrolled using a dose escalation Phase I design, with a starting dose of 1.25 mg/kg/day. The study included patients with a variety of histologies: 16 follicular, 15 CLL/SLL, seven DLBCL, four mantle, four marginal and one waldenstrom macroglobulinemia. Patients had a median of three prior regimens.

Therapy was well tolerated. Clinical responses were observed in 23% of the patients with FL, 69% with CLL/SLL, 75% of patients with mantle cell lymphoma and in 1/7 patients with DLBCL. Because the MTS has not been reached, dose escalation continues. Thus, PCI-32765 has a favorable safety profile with a promising antitumor activity. This activity will be confirmed in future Phase II studies.

Several important studies were presented at the ASCO lymphoma oral session.

In the first presentation, G. Salles from France presented the long-awaited data from the Primary Rituximab and Maintenance (PRIMA) study in newly diagnosed patients with advanced stage follicular lymphoma (FL) requiring therapy. This GELA-sponsored international Phase III study investigated two years of rituximab (R) maintenance in FL patients responding to first-line immuno-chemotherapy consisting of either eight cycles of R-CVP, or six cycles of R-CHOP or R-FCM (plus two additional rituximab infusions). The study was initiated in 2004 and enrolled 1,217 patients from 25 countries at 223 centers. It completed enrollment in April 2007. 


Younes Small.jpgPRIMA results

There were 1,207 evaluable patients treated with RCHOP (n=885), RCVP (n=272) or RFCM (n=45), and 1,018 responding patients were randomized to either rituximab or observation (513 observation, 505 rituximab maintenance). Median follow-up was 25 months from randomization (31 months from study entry).

There was a significant (stratified log-rank, P<.0001) improvement in the primary endpoint PFS, for R-maintenance (hazard ratio [HR]=0.50; 95% CI [0.39-0.64]; two-year PFS 82%; 95% CI [78-86%] vs. 66% [61-70%] for observation). An independent response review committee confirmed the significant improvement in PFS in the R-maintenance arm (HR=0.53 [0.41-0.68]). Time to next anti-lymphoma treatment, as well as response rate at the end of maintenance or observation, were significantly improved in the R-maintenance arm. Remarkably, the benefit of rituximab maintenance was observed in all subgroups, regardless of type of induction therapy, age, FLIPI score, or quality of response (CR vs PR).

The authors concluded that the PRIMA study provided evidence for a new standard of care for FL patients in need of treatment.


More promising news

In a different study, R. Pettengell examined the role or rituximab for in vivo purging and as maintenance after autologous stem cell transplant (ASCT). From October 1999 to April 2006, 280 of a planned 420 patients with rFL in first (n=16), second (n= 222) or third remission (n=41) who achieved either a complete remission (n=83) or a very good partial remission (n=196) to induction chemotherapy, with limited bone marrow infiltration (<25% B-lymphocytes), underwent a single randomization in a 2x2 design to RP and RM, n = 69; RP, n = 72; RM, n = 69; No R n = 70.


The findings

PFS at five years was 54.3% versus 47.8% for in vivo purging versus none (logrank PFS; p=0.20; HR 1.23, 95%CI: 0.89 - 1.72). PFS at five years was 58.8% versus 42.6% in patients receiving R maintenance versus none (logrank PFS; p=0.02; HR 1.50, 95%CI: 1.07 - 2.09). PFS at five years was 54.8% versus 37.6% in patients receiving R purging and maintenance versus none (logrank PFS; p=0.05; HR 1.44, 95%CI: 1.004 - 2.05). The success of salvage therapy is reflected in an overall survival at five years of 80.8% (95% CI: 75.5 - 85.0). Conclusions: This study shows that peri-autograft, R in vivo purging and two years maintenance post-autograft gives a superior PFS compared to no rituximab.

 

Collectively these data demonstrate:

• Rituximab maintenance after induction with R-chemo in patients with advanced stage FL improved PFS


• Rituximab maintenance after ASCT in rituximab-naive FL patients in second or third remission also improves PFS


However, it's important to keep in mind that:

• This data is applicable for patients with FL. Previous randomized study failed to show benefit for rituximab maintenance after induction with RCHOP in patients with newly diagnosed diffuse large cell lymphoma

• We still do not know if giving rituximab maintenance for longer than two years would produce better outcomes or more toxic effects. So for now, if one wants to use rituximab maintenance, one should give it for two years, unless on clinical trials.

 

 

Anas Younes, M.D., director of Clinical and Translational Investigation in the Department of Lymphoma/Myeloma at M. D. Anderson, takes us into his lab where he's researching new targeted therapies for people with Hodgkin and non-Hodgkin lymphoma. His focus is on identifying opportunities to cause cell death or slow the growth of cells for certain tumor types.

He identifies the process involved in getting these targeted therapy drug combinations from the lab into Phase I clinical trials and eventually into standard treatment. 




Younes.jpgAnas Younes, M.D., is a professor in the Department of Lymphoma/Myeloma in the Division of Cancer Medicine. For more information about targeted therapies for lymphoma, you can contact Younes via e-mail, Facebook or Twitter.
 

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NYT_MindyL.jpgIt's a matter of time. I have no doubt about it. The human will, determination and intellect that invented electricity, the phone, the radio, airplanes, the polio vaccine and penicillin, and that put a man on the moon, will definitely find the cure for cancer. Yet, I agree with most, including those who expressed their frustration in the recent New York Times article, that the war on cancer is taking too long to win. It's a war that we have to win. 

According to the American Cancer Society (ACS), 1,479,350 people in the United States will be diagnosed with cancer this year, and it's expected that 562,340 will die from it. In fact, cancer is the second most common cause of death in the U.S., accounting for 23% of all deaths. This means that one of four people living in the U.S. will eventually die of cancer.


These numbers are even more dreadful when you consider the global impact. The World Health Organization predicts that the number of people worldwide living with cancer will rise from about 28 million today to about 75 million in 2030. The challenge is so big, and those of us on the front lines have no illusion of what we're facing. The New York Times article clearly articulated this challenge.

But to balance these dismal statistics, one has to keep in mind that more and more people survive cancer every year. In 2005, the ACS estimated that more than 11 million cancer survivors were in the United States, and this number continues to increase. 

In my own subspecialty, there are many success stories. For example, over the past decade, the expected survival of patients with indolent lymphoma has increased from an average of eight years to 15 years. For mantle cell lymphoma, it increased from 1.5 years to more than five years, and for Hodgkin's lymphoma the cure rate improved from 30% in 1960 to almost 80% today.  

More broadly, after almost three decades of a stalemate, cancer mortality is starting to slowly decrease. Furthermore, our knowledge of the basic molecular and genetic structure of cancer cells has exploded, identifying new therapeutic targets. A decade ago, only a few drugs were in development for cancer. Today, there are more than 800 drugs, with more coming. So I'm confident that we're on the right track, and it's only a matter of time until we find the cure.

So how do we speed up the process? In my opinion, one of our biggest challenges is the inadequate participation of patients in innovative clinical trials. The public is rightly expressing frustration on the slow progress. But to demand and expect speedy development, they also have to actively participate in clinical trials. With an average of less than 10% of cancer patients participating in clinical trials in the U.S., one shouldn't be surprised that the field is moving forward at a slow pace. 

When I read the New York Times article, I was concerned that, despite the challenges that we all face in the war on cancer, a message of hope may have been unintentionally missed. So I posted the article on my Facebook page and asked my followers, many of whom are patients and cancer survivors, to comment.

To lead the discussion I stated, "While I agree that there is so much work to be done, the article should have provided a more balanced picture of the many patients who are cured of cancer and are living a normal life with their loved ones. I also think that we need to move away from the currently available harsh treatments that are debilitating. We need to develop more gentle targeted therapy that are effective but maintain a good quality of life ..." And here are some of the comments that were posted:

"I can see and understand your point of view, Dr. Younes. At the same time, I'm also glad that the author expressed the gravity of the cancer battle. Too often these days, I think, people who haven't been touched by the disease assume that modern science has evolved to the point that cancer is uniformly curable with one shot. That belittles the gravity of the malady and the fight patients wage each and every day. If this article informs that viewpoint, I'm grateful. That said, I do agree with you that there is great hope, and that's what we must focus on to advance treatment and management of cancer. Thank you, speaking from my heart and as a survivor, for your efforts on that front!"

"I could not agree more Dr. Younes - the article really focuses on the most difficult cases ... but that is why the people with difficult cases come to MD Anderson - b/c MDA will stop at nothing and will always give you hope ..."

"My time at MDA was the best medical experience I've ever had. Ironic, given it was related to the worst diagnosis I've ever had. Thanks for sharing!"

Having worked at M. D. Anderson for the past 16 years, I know that the message of hope prevails on everyone's face and is implanted in everyone's soul. I see it on the faces of everyone who works here, from the president to the cleaning crews. After all, it's this spirit of optimism, dedication and hope that will help us eliminate cancer in Texas, the nation and the world.

Younes10_06final.jpgEvery October, scientists and the public from around the world eagerly await the announcement of the winners of the Nobel Prize in Medicine. This year, the prize was given to three U.S. scientists for the discovery and identification of telomeres and telomerase, a process that seals off the tips of chromosomes like the cap on the end of shoelaces, and is a key to understanding both aging and cancer.

Telomeres are essentially caps that protect the ends of chromosomes. The telomerase enzyme determines the length of the caps. The longer the caps, the more frequent the chromosomes can be copied, therefore, controlling how often the cell divides.

The potential impact of this discovery is obvious. Inhibiting the enzyme activity can reduce the cell capacity to divide, a hallmark of cancer. In aging cells, the caps, or telomeres, become shorter. Thus, maintaining telomerase activity may prevent aging.

The Nobel Committee cited the scientists' work that was published approximately 30 years ago (telomeres in 1978 and telomerase in 1985). This means that two of the recipients were in their 30s and one was in her 20s when they made these discoveries.

Intriguing selection process
The secretive nomination and selection process of the committee remains intriguing, and continuously generates rumors and fascinating stories. According to Alfred Nobel's instructions in his will, the committee members should always be selected from the Karolinska Institute faculty in Stockholm.  In 1901, the committee included 19 members. Today, it includes 50. A total of 195 individuals have received the Nobel Prize in Medicine.

I visited Karolinska Institute in 1999, and had the opportunity to meet with its president, Dr. Hans Wigzell. At the time, Dr. Wigzell was the chairman of the Nobel Assembly that awards the prize in medicine. The following year I invited him to visit M. D. Anderson and to give a lecture on his scientific work in immunology. However, my hidden agenda was to get him to meet with our young medical oncology fellows, to discuss the award and to inspire them. He graciously accepted the invitation.

As planned, Dr. Wigzell met with our fellows in a small conference room over coffee and bagels. The informal meeting lasted 90 minutes, and the discussion spanned many interesting topics and anecdotes regarding the Nobel Prize. Although he couldn't reveal any secrets, he provided very important facts and insights.

The first fact was that nominations are kept very secretive and are not released to the public. You know that you got the prize when someone calls you from Stockholm early in the morning, shortly before the announcement is made public. So this is not like the Oscars. Although several investigators are nominated on a short list, the names remain secret and, therefore, there is no reward or even an acknowledgement for being nominated. Nothing to write about in your C.V.

The second fact was that no matter how important the discovery might be, the award is given only to a living scientist. No award is given after death.

The third, and most important observation that I recall from our meeting with Hans Wigzell, was that the majority of awards were given to scientists for discoveries that they made when they were young, mostly when they were in their 30s. A remarkable observation that strongly endorses the notion than many creative ideas come from young, unestablished investigators.

However, these discoveries have to be validated over time, and thus the awards are frequently given 20-30 years after their discoveries. This year's award was no exception.

Funding the young still critical
As research funds continue to decrease, a debate in the scientific community is focusing on who should get more research support: established senior investigators or new junior investigators. No one argues that established senior investigators should continue to receive research funding. However, a quick look at the history of the Nobel Prize and its laureates should convince everyone that funding young investigators is also critical for the continued progress through major discoveries that will have the greatest impact on humanity.
 


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