Will radiation oncologists miss the boat?

[RadOnc10000]

The following article regarding anti-CD20 radioimmunotherapy with Bexxar came out in this week's NEJM. While the study suffers from not having a control group and including mostly "favorable" patients, the results are nonetheless very impressive. But there is one thing I find disappointing about the paper above all else....as far as I can tell, none of the authors are radiation oncologists. Will our specialty miss the boat on this exciting (and potentially generalizable) extension of radiotherapy? I think as future radiation oncologists, we should push our specialty to become the leader in this field of cancer care. I know that there are a few leaders in this area that are radiation oncologists, but I think there could (and should) be more. Rather than worrying about the future, we should actively engage it.


131I-Tositumomab Therapy as Initial Treatment for Follicular Lymphoma

Background: Advanced-stage follicular B-cell lymphoma is considered incurable. Anti-CD20 radioimmunotherapy is effective in patients who have had a relapse after chemotherapy or who have refractory follicular lymphoma, but it has not been tested in previously untreated patients.

Methods: Seventy-six patients with stage III or IV follicular lymphoma received as initial therapy a single course of treatment with 131I-tositumomab therapy (registered as Tositumomab and Iodine I 131 Tositumomab [the Bexxar therapeutic regimen]). This consisted of a dosimetric dose of tositumomab and 131I-labeled tositumomab followed one week later by a therapeutic dose, delivering 75 cGy of radiation to the total body.

Results: Ninety-five percent of the patients had any response, and 75 percent had a complete response. The use of polymerase chain reaction (PCR) to detect rearrangement of the BCL2 gene showed molecular responses in 80 percent of assessable patients who had a clinical complete response. After a median follow-up of 5.1 years, the actuarial 5-year progression-free survival for all patients was 59 percent, with a median progression-free survival of 6.1 years. The annualized rate of relapse progressively decreased over time: 25 percent, 13 percent, and 12 percent during the first, second, and third years, respectively, and 4.4 percent per year after three years. Of 57 patients who had a complete response, 40 remained in remission for 4.3 to 7.7 years. Hematologic toxicity was moderate, with no patient requiring transfusions or hematopoietic growth factors. No cases of myelodysplastic syndrome have been observed.

Conclusions: A single one-week course of 131I-tositumomab therapy as initial treatment can induce prolonged clinical and molecular remissions in patients with advanced follicular lymphoma.

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[Gfunk6]

At our institution radiolabeled anti-CD20 antibodies are administered by Radiation Oncologists. It may be institution specific.

 

[RadOnc10000]

At our institution radiolabeled anti-CD20 antibodies are administered by Radiation Oncologists. It may be institution specific.

That's good to hear. I know there are some radiation oncologists who are very interested in systemic radiotherapy, but I fear that they are in the minority. I'm sure there will be turf battles between radiation oncology and nuclear medicine at many places regarding these and future systemic radiotherapies. I think the best way to ensure that radiation oncology will play a future role in this area is to advance research on this topic in radiation oncology departments. Otherwise another specialty will quickly become the "experts" and attract that majority of patients, research funding, and attention. Unfortunately, when there is money involved, people often don't play nice....

 

[RadOncFever]

That's good to hear. I know there are some radiation oncologists who are very interested in systemic radiotherapy, but I fear that they are in the minority. I'm sure there will be turf battles between radiation oncology and nuclear medicine at many places regarding these and future systemic radiotherapies. I think the best way to ensure that radiation oncology will play a future role in this area is to advance research on this topic in radiation oncology departments. Otherwise another specialty will quickly become the "experts" and attract that majority of patients, research funding, and attention. Unfortunately, when there is money involved, people often don't play nice....

I totally agree that by advancing research into these areas, radiation oncologists will facilitate entry into the field, but will by no means ensure its success if radiation oncologists don't contribute to some of the basics of the field, such as discovering new molecular markers on tumors as targets for systemic radiotherapy. Radiation Oncology has traditionally been a more technical field, with trainees and clinicians having a background in physics and engineering, contributing many past and present advances to improve the delivery of radiation. Although radiation oncologists have also contributed significantly in the area of radiobiology and in the basic understanding of how radiation interacts with tumor and normal cells at the molecular level, less intellectual capital has been invested into the understanding of molecular tumorigenesis. Medical Oncologists, on the other hand, has traditionally been a much more basic science field, with lots of time spent to understand the basic mechanisms of things, and their research contributions also advance such understanding. Therefore discovery of new tumor markers, and therefore proprietorship into the clinical utilization of these targets, becomes those of the medical oncologists. I could say that nuclear medicine has also the same basic slant. I believe the field of radiation oncology has evolved tremendously in the past few years, with current residents and researchers becoming more and more interested and focused into the basic sciences of not just understanding how high energy photons interact with DNA, but also into understanding tumorigenesis itself. As more and more MD-PhD's and MD's that pour into the field with a background in the basic sciences, it's natural that the field will evolve in such a way. To be competitive, we have to contribute at the basic level, in order to have prioprietorship at the clinical level in treating our patients. And if that is in the area systemic radiotherapy, there needs to be that kind of "grass roots" effort on the part the field as a whole.

 

[cdf95cro]

In talking to the folks at our institution, the reactions seemed to be that, naturally rad onc would deliver this, since the referral pattern for cancer patients does not typically go through nuc med.

A junior faculty member stipulated that technical or scientific competency has less to do with who gets procedures than with who can get the patient referral first (i.e. cards self-referring caths rather than going to radiologists), and felt that the reason people in rad onc don't seem "interested" in targeted immunoradiotherapy is because there are few appropriate referrals at present, since med onc catches patients for both frontline and salvage chemo, and we see the small monority they happen to refer to us.

 

[Ursus Martimus]

My impression is that the delivery of therapeutic antibodies conjugated to radioisotopes is institution specific. However, I would venture to say mostly handled by nuclear medicine. It is also my understanding that there are new training guideline requirements that require some minimal exposure (no pun intended) to open sources. In discussion with various programs on the interview trail, most programs are farming their residents to participate with nuclear medicine docs for such experience. The sentiments solicited on this forum have been someone less than enthusiastic about how "fun" it is to deliver such antibodies... ie inject, pull back, flush, done. I would hate to be left out of the loop for such an important therapy, but there are such biases agains it. With that said, I have run into only one Radiation Oncologist who is involved in the development of such antibodies, Susan Know at Stanford. I believe there is someone at Michigan with some interest and a group at the University of Washington, as well.

I think there is some exciting work being done by DavidScheinberg at Sloan Kettering on the use of alpha generating suicide mhc tetramers for the deletion of autoreactive T cell in autoimmune conditions. Will this cool opportunity be passed up by radiation oncologists as an opportunity to use their skills in the treatment of a new benign conditions? Probably.

 

[RadOncFever]

Apparently Dr. SE Order has laid out a proposal for systematic training for residents in the area of systemic radiotherapy as part of radiation oncology residency in the most recent issue of IJROBP:

http://www.sciencedirect.com/scienc...ersion=1&md5=24a985422c284d9ac0def4db55f92d64

But refuted by Dr. Wallner et al in a follow up response:

http://www.sciencedirect.com/scienc...ersion=1&md5=7bfec809ef05317e4e90d44027e65243

Although critical mass has not been achieved and it may be premature at present to incorporate such training, I agree with Dr. Order that to be proficient in such a field would require us to also become familiar with the same basics of nuclear medicine that radiology residents have as part of their training. Yes, it may be as easy as "inject, pull back, flush", but everyone can say the same for Linac based therapy: "aim and shoot". There's certainly more than meets the eye. The science and biochemistry behind isotopic labeling of antibodies and small molecules and the dosimetry involved can be complex and I would certainly would want to be as proficient as my nuclear medicine colleagues if I was to enter such a field. I don't think it would be that difficult for those interested to incorporate a rotation in nuclear medicine as part of our residency training.

 

[RadOncFever]

In talking to the folks at our institution, the reactions seemed to be that, naturally rad onc would deliver this, since the referral pattern for cancer patients does not typically go through nuc med.

A junior faculty member stipulated that technical or scientific competency has less to do with who gets procedures than with who can get the patient referral first (i.e. cards self-referring caths rather than going to radiologists), and felt that the reason people in rad onc don't seem "interested" in targeted immunoradiotherapy is because there are few appropriate referrals at present, since med onc catches patients for both frontline and salvage chemo, and we see the small monority they happen to refer to us.

Please correct me if I am wrong but my impression is that radioimmunotherapy is still at the experimental phases and not done outside of clinical trials (save for 131 Iodine ablation for grave's). As a radiation oncologist with a new antibody or isotope that could help you grab a grant for a clinical trial, there shouldn't be a problem for referrals. Anti-CD20 has always been the medical oncologists' baby, so it would make sense that they are the ones making the connections with the nuclear medicine docs for the infusion treatments.

 

[RadOnc10000]

Please correct me if I am wrong but my impression is that radioimmunotherapy is still at the experimental phases and not done outside of clinical trials (save for 131 Iodine ablation for grave's). As a radiation oncologist with a new antibody or isotope that could help you grab a grant for a clinical trial, there shouldn't be a problem for referrals. Anti-CD20 has always been the medical oncologists' baby, so it would make sense that they are the ones making the connections with the nuclear medicine docs for the infusion treatments.

Both Bexxar and Zevalin are FDA approved. Bexxar used to be indicated only for patients with refractory disease who have relapsed, but has recently been extended to refractory or relapsed patients (http://64.233.167.104/search?q=cach...scape.com/viewarticle/497469+bexxar+fda&hl=en). Since they are both approved, off label use is of course possible. With the recent NEJM paper showing impressive efficacy as first line therapy, it's not hard to imagine that this may become a standard treatment for many (and even the majority of) patients.

I don't see why oncologists should be more willing to partner with nuclear medicine docs than with radiation oncologists. We work with them more closely, see them more frequently at tumor boards, share more patients with them, etc. It is true, however, that the radiation oncology community does not have a real history in the area of systemic radiotherapy. That's what I'm hoping will change, and I think it can if enough of us "young" rad onc docs make it a point to learn about it and become involved in it. If it means that we have to do rotations in nuclear medicine departments for now, then so be it. Once we are comfortable with treating patients with this modality, we can teach those that come after us. And I think you're right, RadOncFever. It is just as important that we contribute to the basic and clinical research that goes into developing these agents. If we are seen as research leaders in this area, we will be more likely to get a bigger chunk of the referrals.

Also, I think that people who are not interested in systemic radiotherapy because they are not interested in the "inject, pull back, flush, done" process are a little short sighted. We do boring, repetitive things in medicine (and as hard as it is to say, even in radiation oncology) all of the time, but if they benefit our patients, they are worth it. Plus, extending radiotherapy to treat systemic disease is far from boring in my opinion. It has the potential for curing thousands of patients, something that should excite any current and future radiation oncologists. If I need to "inject, pull back, flush" in addition to (or instead of) coming up with an external beam plan to best serve a patient, then I'll be more than happy to do that...

 

[RadOncFever]

I can't agree with you more. The prospect that radiation oncologist could be involved in not only locoregional treatment with EBRT but also systemic treatment for metastatic processes (other than simple palliation for localized pain, bleeding, etc) as well as the possibility for systemic prophylaxis for recurrence (such as seen in many cancers such as locally advanced breast and prostate cancers) is very tantalizing. I think that could only strengthen our field as a whole by such approaches.

 

[stephew]

1) its very institution specific
2) its an interesting study but its hardly definitive. (just by way of commenting on the trial) and
3) remeber: gleevac; herceptin; adriamycin; etc etc. the magic cure aint here yet. I hope it comes but as near professionals we all must learn not to get carried away with the Gene/Therapy/Chemo/RT technique of the month. Its not boutique.

 

[RadOnc10000]

1) its very institution specific
2) its an interesting study but its hardly definitive. (just by way of commenting on the trial) and
3) remeber: gleevac; herceptin; adriamycin; etc etc. the magic cure aint here yet. I hope it comes but as near professionals we all must learn not to get carried away with the Gene/Therapy/Chemo/RT technique of the month. Its not boutique.

I agree that this trial has problems. Even the authors don't claim that it is a "magic cure" and I sure don't think it is. But it is a potential example (if the data hold up in RCTs) of how systemic radiotherapy can be effective, even as a first line agent. If such therapies can induce long term remissions, then we could hold some of the other modalities (chemo, external beam, etc.) for when patients recur (i.e. sequential and multimodality therapy). Or if nothing else, it gives us one more tool that we can use to help appropriate patients. While this story is far from over, it seems promising enough to me that it should interest radiation oncologists. I know not all (or probably even most) will care, but I'm glad to see that some already do. And of course it's possible to be interested in and even excited about a new therapy without "getting carried away." We owe it to our patients to continually try to improve the treatments that we can offer them.

 

[stephew]

i think its a part of the arsenal but not at this point anywhere near being a substitute of chemo, external beam etc. Anyway radonc and nuc med both tend to do these.