I want to emphasize that lymphomas are relatively rare diseases. There are many randomized trials that have influenced practice. However many of the cases we see do not have randomized trials that support good data for making decisions and so there are different opinions especially when there are few data. I want to tell the importance of experience in our rationale approach. This helps us in treating patients and often there is no right answers. You see some differences between the cases. The opinions from the panel will be important. Some cases are a little more challenging but they have been selected to represent cases that you might see in your practice.

This issue will be a little more focused on NHL and we mention the audience texting. One of the things that we try to do this year and prior years is to show cases of recent publications.

This is what you should be able to do after this session so I will not read this.

This is a patient that I recently saw. He is a 53 old male presenting with a right groin mass. He was referred by his primary care physician to a surgeon who performed a laparoscopic hernia repair but after the procedure he still had a mass. So he underwent a CT scan which showed a confluent nodal mass of the inguinal – sacral region on the right of 3.7 cm in greatest dimension.

He then underwent an excisional nodal biopsy which revealed a grade 2 follicular lymphoma. He underwent a PET CT scan which showed no other abnormal areas of FDG uptake. There was a post – op uptake in the surgical bed. He had a negative BM biopsy. He was then seen by a local oncologist who recommended observing him. At that time he was referred to us for a second opinion.

The first question is what you would recommend in this situation. Would you choose observation as suggested or CHOP chemotherapy or chemotherapy and radiation therapy, IFRT, involved field and adjacent nodal group RT.

So 73% voted for IFRT.

So anyone in the panel wants to comment?

IF is a term undergoing evaluation and re – examination. There is a group of RO who have a great interest in lymphoma. They try to define the appropriate definitions in different scenarios. They adopted the term involved site radiation which implies for the most part irradiation of the initially involved LN regions with appropriate extension to define the CTV and the PTV depending upon clinical circumstances and trying to move away from the terminology involved field which suggests rather regimented designed fields based on anatomic orders that may not be completely appropriate.

For example, in this case if you say involved field you would just treat the inguinal femoral area and stop at the inguinal ligament. Another panelist would treat into the iliac area so my choice would be four and a half. While treating I would not go to the bifurcation but I would treat a little bit more that just the inguinal femoral area.

The next question is what dose do you use. None, 2 x 2 Gy, 24 Gy, 30 Gy, 36 Gy.

The majority voted for 30 Gy, close to 73%.

I want to comment on that dose range.

My answer would be number 4 in a case where RT is curative and intense. We have been describing 30 Gy in 20 fractions. My answer is that there is too much difference between number 3 and number 4 really. We have been restricting boom boom for this case. It is extremely effective.

We do have a study for this. There is a phase III trial from Great Britain for indolent lymphomas.

You mean the 24 Gy compared to 40 - 44 Gy. They really do not look at 30 Gy but I agree that 24 Gy is effective as 40 - 44 Gy.

I can comment on that. Actually we do believe this. At MD Anderson we started and we enrolled other centers to join us and the way we do it is we give 24 Gy plus minus Rituximab. I can comment on the reason why we added Rituxmab to it. Basically the definitive impulse is 24 Gy.

I think that the guidelines from the national lymphoma radiation oncology group will come out as 24 - 30 Gy range.

So the patient received 30 Gy and here is the field. In the clinic we quickly changed this treatment plan. Here is the other field on the axial.

Would you include the external iliac LN?

The inguinal nodes are very interior so you could use a wedge are for example but we were concerned about the external iliac chain. With the dose we use we go AP PA sometimes wedging a little bit anteriorly. Because of some concernes about the distal external iliac nodes. We did include the external iliac chain. The other thing we do is we use double blocking. Is there any question about testing the field under the normal block. So instead of 3 and a half we got a 3% dose. So we put the anal c blocking.

Why I like this case. We have the forward case. It is quite shocking how often our medical oncologist refers to us these patients, who received either Rituximab alone or a recommendation for nothing. I want to go back and look at the historical data and this is from Stanford. We all know the original report of 177 patients with stage I and II as shown with median follow up of almost 8 years. The OS and RFS are listed but even in 20 years the RFS is 40%. Most of the recurrences are early within the first 5 years.

This is the study you are referring to looking at randomized doses of RT. This was a larger study which included both aggressive and indolent lymphomas. Patients were randomized to 24 Gy vs 40 - 45 Gy without any difference in the overall response rate, complete response rate, PFS, OS.

This is a paper that we did from the NCCN database at Dana Farber. There are 7 academic medical centers who were part of the database. We looked across all the centers. How many patients with grade I and II follicular lymphoma received RT which is a level 1 recommendation by the guideline panel.

Here you can see there are 100 patients with stage I that we identified within the database. There is a significant variation among the different centers. You can see that less than 25% received RT alone. There is a fair number of patients who were observed. Perhaps some of these patients had intra abdominal disease or disease that was not easily accessible. We found that it is interesting and worth funny now.

There is a recent study that came out. A vary large study from the SEER database looking at more questions. You can see how many patients with localized grade 1 and 2 follicular lymphoma received RT. This data look quite similar. This is from SEER but we saw the academic medical centers. In that fewer than 40% of patients across multiple decades received RT.

This is the lymphoma specific survival from that study. You can see it is a very large study with 6400 patients. 2200 patients received RT, 4300 did not. There was a significant benefit both in terms of LSS and OS in this particular study.

So here we do a multivariate analysis including a number of factors for DFS and OS. You can see that age in stage I vs II were predictive but the radiotherapy on the bottom was highly predictive and the DFS was very significant as well as OS.

This are data that were presented at Lugano this year from Princess Margaret. It is a very large series of 700 patients with stage I and II follicular lymphoma treated with 20 Gy with a long median follow up of over 10 years. About 182 patients received combined modality therapy. The majority of them received R - CHOP based therapy. patients to receive chemotherapy were more likely to have stage II grade III high LDH or bulky disease. But in the group 526 patients received RT alone. When you look at the outcome they really look very good. The median dose is about 30 Gy.

The vast majority of patients had a complete response. The 10 year relapse rate was 50%, which fitted better than the original data from Stanford. The local and marginal recurrence rate are very low. The 10 year OS for the patients who received RT alone is 65% in the combined modality therapy group. It was not better than 66%. The lymphoma SS was similar across both groups at 80%. Very low grade of transformation for this follow up at 5.9%. For the patients who recurred (288 patients) only less than half required chemotherapy at 10 years post diagnosis suggesting that this means a distinct biology for the patient with more advanced follicular lymphoma.

So there are a couple of questions. One is when we give 24 Gy vs 30 Gy I think that some of these decisions are based on the fact that the disease was excised completely or if there is large disease even at an early stage. It depends a little bit on when the radiation oncologist had his training. Those who were trained long ago tend to give higher doses.

There is also a question about the definition of IFRT. Inguinal lymphomas are treated up to the SI joints. I think we do not use this trick for IFRT any more. I think we adjust the fields a little bit.

Using RT alone for treating a patients like this I would extend my field at least 5 cm proximally from where the disease was based on PET or CT or both or physical exam. In this scenario of combined modality therapy then I do not worry about those extensions as much. I would treat more tighter fields but when you use radiation alone you have to put wider margins.

In the trial they gave 24 Gy in 2 Gy fractions. I think there is no difference between this and 30 Gy in 1.5 Gy fractions.

I want to ask my own question. We never advocate aggressive surgery. Sometimes patients come with 1 or 2 neck LN that were removed completely and the post op staging shows no evidence of abnormal LN at CT or PET. Are you more open to discussion about observation in that scenario?

I would not. I think there is the risk of recurrence in this area. It is the neck area and you are concerned about several functions. You can drop the dose below 24 Gy in that setting.

I would not agree with observation for a simple reason: many times you would see patients with very small LN, very low SUV under PET scan. But if you are lucky enough to do an excisional biopsy on them they look non specific by radiological definition but then they come back with follicular lymphoma. This comes accordingly to what dr Haffty was saying. When you use radiation, not everything you see or you do not see on your imaging means it is or it is not there. Therefore yes we do involved sites but then we do a more careful look to include that area with more generous margins because I am chasing those small LN that look so unassuming on imaging. So the short answer is that you have to treat.

We presented a case 3 or 4 years back, that was similar. Things have changed so I want to present this case. It is a little bit unusual but many of the people in the audience see cases like this in their practice. RT makes a big impact on the outcome.

This was a 72 year old man that we saw with a 10 year history of rhinoplasty and obstructive sleep apnea. He then developed nasal fullness. CT revealed the soft tissue mass in the left nasal cavity. There was no biopsy at the time. He was treated with antibiotics and the symptoms resolved. Then 6 months later he developed worsening of the nasal fullness, occasional epistaxis, increasing discharge. He had an ENT exam at that time under anesthesia that revealed a diffuse inflammatory process of the left nasal wall. There was a very friable inflammatory pseudo mass with fluid that was excised. This pseudo tumor appeared to extend to the nasal floor. The entire lesion was not excised.

Pathology revealed an extranodal NK T cell lymphoma nasal type. The Ki 67 was up to 70% in some areas. PET CT and contrast CT one week post surgery revealed node disease outside of the nasal area. The PET was mildly positive at the surgical site.

He repeated an ENT exam 2 months later and it was normal. There was a delay because of surgical complications. At the ENT exam nothing appeared abnormal. We obtained a MRI at that time because we wanted to have an idea of the extent of this disease.

We should recommend RT alone 45 Gy, 54 Gy, CHOP followed by radiation, radiation 45 Gy followed by chemo, radiation 54 Gy followed by ChT.

Many studies that were published so far showed that ChT and typically CHOP is not effective in NK cell lymphoma. That is why recently we reversed the sequence and we started with radiation followed by ChT. There are 2 studies coming from the canadians and the japanese that actually use concomitant ChT and RT. So based on that actually we just started a prospective study at MDA using 54 Gy and concurrent ChT. Yes it is toxic but then this is a disease that is locally advanced. If it has to come back it does it locally so your local treatment is probably the most important thing.

In terms of ChT CHOP is well expressed at MDR genes that may pumps the ChT. I think that newer regimens using MTX or L asparaginase are important. In addition there have been studies looking at checking EBV viral loads before you treat a patient. They can be predictive of distant recurrence. That makes thinking about it. Absolutely the radiation needs to come early or you loose your local control and it is a really morbid disease.

We had the CT to evaluate the lesion. We used IMRT for this case. We also have a terrific neuro radiologist that will comment. We have covered anything suspicious. This is the lateral view.

I have another comment. Imaging is important. That is why you have to use all the imaging available to you. For instance we use the PET scan that will show the activity which sometimes could be inflammatory or could be disease. Then we use the MRI for the soft tissue and then we use an enhanced contrast CT for the bony invasion. The 3 of them will be fused most of the time with the planning CT. The main reason is that you have to have a very low threshold to include any area that looks suspicious into your field. Most of the data that comes from the asian countries actually included all the sinus. I would think that the reason why we do that is not that we have to include all the sinus is maybe that they had not enough imaging ability to figure out what to include and what not. That is why the local control was high when they included all the sinus.

This was difficult in this case because we had only one study that was really helpful at the time we were doing this. But I agree with the concept of multiple image fusion.

When a sinus cavity has been filled then we cover the whole sinus. So if the tumor is perforated to the bone medial wall but the maxillary sinus is not completely filled we will assume that it is contaminated and treat that as CTV. We do not treat all the sinus unless there is some evidence that the sinus wall is penetrated.

I want to show you a couple of views because this case involves the medial wall, the orbit or the lacrimal gland or the duct. In this case it is more central but you have to be very careful of the total dose and the dose you give the optic nerve and the retina. In this case we were lucky so we just had a little bit of the left eye orbit. I show you a couple of pictures.

We had some discussion a few minutes ago about the 3 different regimens that are used. There si a number of publications using these various regimens. I think the problem is CHOP plus RT is not very good. The data show sandwich regimens.

In this case since it was a 72 year old patient we did not feel good to give chemo at the same time. We gave RT and then chemo.

I think that at ASCO 2013 there was a phase III trial on this disease. It compared CHOP vs a more aggressive chemo regimen. I think it is the second at the bottom. It suffered from the fact that they put RT at the end of the treatment so it was not a perfect study. There was a dramatic survival advantage for the more aggressive chemo not - CHOP. So I think there are data that endorse the fact that it is good not to use CHOP.

Most of the studies that use concurrent CRT ended up while breaking the radiation course which we do not like at all or ending short of 40 Gy which again we do not recommend. One has to use the mentality of HN when treating this disease and go through it and afford the side effects because if you really finish at least at 50.4 Gy with no interruption it is good.

There was a lot of discussion about that particularly there were abstract at ASCO. I think a lot of people knows it is difficult to lead the radiation to the end. There was not a OS benefit. It was a regimen the no one really uses. It has a little bit of PFS in the original study but it was not statistically significant. I think people will be disappointed by the results of the study.

There was a survival advantage. People were very surprised that the study was presented because no one felt that the radiation should go to the end and it was giving a bad message.

There was very very little advantage in PFS in the intense arm locally. I agree with you.

I had a slide here. There is a study from China on 84 patients with nasal NK T cell lymphoma. Most patients got combined modality. The chemo was CHOP for almost all the patients. It showed significant advantage giving radiation before ChT and a significant advantage in terms of DFS and OS using doses of 54 Gy or above vs dose less than 54 Gy. I think in terms of RT you want to make sure that you give an enough high dose.

Do you have any comment about 45 - 54 Gy?

We give 54 - 55 Gy. Before that data came out we would give 45. We occasionally saw recurrences in 3 or 4 years. That was a disaster.

I give 50.4 Gy. I think the NCCN guidelines say 50.4 - 54 Gy.

If I have the sinus filled I am doubtful that there is disease in it. Maybe there is thickening or inflammation. I paint the dose because I am using IMRT to give 54 Gy to the area of low suspicion. Then I go up to the definitive dose where I know there is the disease.

There is a very nice review on Blood this year. How I treat NK T cell lymphoma; it is about the radiation dose.

I want to present a case of mantle cell lymphoma. It is in 2 parts, an advanced stage and an early stage I will start with a 70 year old patient. It is a stage IV mantle cell lymphoma. In 2007 he had multiple previous therapies. He underwent he regimen that is used at MDA, the leukemia like regimen that they used for mantle cell lymphoma. He got into remission for quite some time then he came back with a relapse. He was treated with Rituximab then he relapsed then he came back, he was treated with Rituximab, then he came back with a relapse. Then they used hyperfractionated Ciclophosphamide. Then he presented to me with troubled swallowing because of the mass that you can see in his throat. Since he was pancitopenic with a low bone marrow reserve I treated him with radiation. The question is what would you recommend observation, additional ChT, RT 2 Gy x 2F, RT 20 Gy, RT 40 Gy.

The majority chose 20 Gy. This is what I did. The patient is completely cleared. Then he presented again.

Sometimes mantle cell lymphoma is very radiosensitive. I would give 4 Gy in this setting.

I just finished treating a patient with 4 Gy and he had a CR.

I learnt over the years. Mantle cell lymphoma was such a new disease to us. I kept on dropping. Now sometimes I give 4 Gy, 8 Gy and you have a nice local control.

Then he presented again with that mass in the back. You can see it on the PET scan. I gave him again 20 Gy. He went into remission. You can see on the PET scan it went away after 20 Gy. He presented again with a mass you can see in the orbit and in the nasal area. I started treating him and after 8 Gy his eye is completely open. So in these years I went on dropping the dose. I am a big believer that mantle cell lymphoma is extremely radiosensitive. You do not need to use a high dose.

We know from multiple publications for example form MSCKK that there is a high response rate. They investigated 21 patients, 38 sites. The overall response rate was 100%. There was a complete response in 64% of them. The average time to response was 20 days which is what you usually see. They immediately melts when you give the radiation. The median dose was 30 Gy, with a range between 10 to 45 Gy. Now at MSKCC they use a lower dose.

At this meeting something similar was presented form the MSKCC. They presented a paper with 41 patients and 68 sites. The response was a CR in 57 sites which is 83%. PR in 8 sites. The RT dose ranged between 20 and 40 Gy. I am more convinced now to drop the dose to lower than 20 Gy.

I will also present a 60 year old gentleman who was diagnosed of a stage I mantle cell lymphoma of a high left cervical node. The PET scan did not reveal any disease as well. The bone marrow biopsy was negative. The question to the audience is would you do ChT alone, ChT and RT to 20 Gy, CRT 30 Gy, RT alone 20 Gy, RT alone 30 Gy, RT alone 40 Gy.

Did you investigate the GI tract?

It is part of the classic investigation as you do an endoscopy and a colonoscopy.

The majority would give ChT and RT 20 Gy. I think the opinion is divided when it comes to stage I - II. There are people who believe that RT alone would be fine. The majority in some centers would go with ChT without consolidation with RT. I would like to hear your opinion.

The algorithm we follow is to give combined modality therapy and we turn away probably with R - CHOP or something similar followed by radiation. I would give 30 Gy in this setting even though it is a radiosensitive lymphoma. In combined modality 20 Gy is as good as 30 Gy so I give 30 Gy.

We do the same. We use R CHOP. Now we use BR which is better than R CHOP.

It is the same combined modality with involved field 30 Gy.

I wanted to show you this study we submitted to ASH. It is form multiple centers around the world. We collected all the cases with mantle cell lymphoma stage I and II. The take home message was that radiation is effective in combined modality but in some instances also when you give RT alone it would lead to the same outcome.

Did you do any mutivariate analysis. One may think that there is some selection bias in those who got combined modality.

Sure. The selection bias was the reason why we ended up examining the cases that came to the RT department. Now we are collecting all the cases that come just to the door of the institution and how they were distributed. That is what we are doing right now. specifically for the selection bias.

30 Gy. I think we have a consensus on that.

Some cases with RT alone had very good 5 year DFS.

I think the message that we want to give the audience is mantle cell lymphoma is a forgotten disease for the radiation oncologist. It is extremely sensitive to radiation especially when the medical oncologist is out of options or he can not give ChT alone. I think that maybe there are 2 MCL. That is my personal opinion. There is the MCL that is aggressive like leukemia. There is the MCL that keeps on coming back for many years. For this latter one I think that the role of local treatment with RT becomes relevant.

I think there are some correlatives that we know like the KI67 fraction. It is very predictive of biological behavior. Those who have KI67 p deletion tend to have very aggressive disease. There is a number of other correlatives that are coming out. They may be predictive and help you to pick up patients. The BTK inhibitor is coming out early next year. It will change the way we treat MCL.

When stage I or II MCL present in the HN area for some reason they do better than when they present in the rest of the body. We ended up with that.

Despite those good results you see for RT alone I would be uncomfortable treating a patient with MCL with RT alone. I would prefer combined modality.

It strucks me that we do not see a lot of these cases because most of the times they are stage III or IV when they present. So you have a disease that is systemic. It takes a lot of effort to show that there is a subgroup of patients that are curable with local treatment. I agree that you may gain something using systemic therapy as well.

I think we should discriminate that there is a subgroup that present with HN disease such as the eye or the NP. Honestly they behave completely differently than your regular MCL that comes with blood involvement.

You have to follow these patients for a very long time. We had a patient that we treated 10 years ago. He recurred with systemic disease. We thought it was one of these cases. It was a BOT. He got combined modality 10 years later. Now he has very aggressive disease everywhere.

My conclusions were that MCL is very sensitive to radiation. Low dose radiation can achieve a CR (20 - 24 Gy). In my practice I would use 8 - 10 Gy. It is an effective and tolerable treatment for palliative reasons. It could be used also in combined modality if you have early stage patients.

I would include 4 Gy on that list of low doses that can achieve a CR. When I prescribe 20 Gy over 2 weeks and I see the patient at the end of 1 week, even quite big LN can be completely gone. The point is do I have to go on.

We have 2 minutes.

One of the questions for this case is what about R CHOP followed by high dose ChT. I think it is a question more for stage III IV. I will be interested in the panel thought about BMT for this disease.

We looked at the NCCN patients data base and compared patients who got Tarceva and ASCT. There were differences in PFS but there are a number of randomized studies including those from the nordic group. There are randomized studies from France. They suggest that ASCT probably improve PFS. It is unlikely that it results in long term cure so maybe there is a small subset of patients with low KI67. I think that novel drugs (Abrutinib) are promising. Maybe there are data from Germany in old patients with CHOP and R in maintenance. Those studies look really good and one wonders if maintenance R or some type of maintenance maybe equivalent to high dose ChT and ASCT as rescue. Those studies are not really well done.

There is something that you see potentially. At PMH patients with MCL are treated with a protocol using R CHOP and a TBI containing ASCT regimen.

We still do it for our patients.

There are a couple of questions. Can IMRT lead to underdosing of important regions. All data come from large field era. The second question is how much extension. We discussed some of the concerns about using multiple scans to fuse treating any area that looks suspicious at all because I think we are aware that the price that you pay using IMRT is the rapid fall off at the edge of the field. The extension question is a little complicated because I think it depends on how close your normal structures are. I think that if you are in an area where you are not worried about with high doses I think that you can use more expansion than you would in other areas.

Using IMRT for this case is almost a must. I would give 54 Gy. We are in a fortunate position as you can keep the mean dose to salivary gland less than 24 Gy where patients treated to 70 Gy for SCC can not achieve it. You really can reduce the morbidity substantially. You can use the chiasm dose less than 50 Gy. The merits of IMRT in this case are far away the concerns.

About the N case the survival is 60 months.

I present the case of a 46 year old female presenting with a large mediastinal mass showed on CT scans. She is found to have a PMBCL stage IIa with an elevated LDH.

Which is the optimal ChT.

Do we really need to go to 8 cycles of R CHOP.

In the era of PET if you do not have a CR after 6 cycles you do not have to go to 8 ones.

The NCCN panel says to go to 8. You do not know how much disease is left, the most part is cured. In this disease RT is effective if you use R CHOP.

There are no randomized trials about the optimal ChT. There are 2 controversies, one is about the addiction of R. The other is about the dose dense so called third generation protocol. The question is if they are more effective than for example R CHOP 21. These is one retrospective study that compared patients with this disease treated with CHOP versus third generation protocol. The inferior DFS on that curve is with R CHOP. The 80% DFS is what has been seen with the dose dense protocol.

Here there are other retrospective studies comparing CHOP with third generation protocols. If you look at the middle column you see RFS and EFS. The CHOP regimen is inferior. This led many people to conclude that TGP are preferable. However many people in the room also recalled that this was the same argument that was made for DBLCL again base on retrospective data. That was disproven in a randomized trial.

The other issue is if or not R may be better. This are data from the NIH shown some time ago. On the left there is the dose adjusted EPOCH and on the right are the EFS and OS when R is added. You can see the improvement when you add R.

With R CHOP and RT the EFS is 75 - 80%.

This regimen received a lot of attention over the last year and so what I want to do is update you about this. Dose - adjusted EPOCH plus R is a combination of agents that are listed on the top. With each cycle the dose is increased depending on the neutrophil count. It depends on the dose adjusted components of the regimen.

This regimen is more difficult to give. R CHOP is given one day to an out patients. Dose adjusted R EPOCH is 5 days. There is a 4 day continuous infusion of adria etoposide vincristine and R at the end. Many patients can go home with the pump but it is not easy and you drive people to be neutropenic. With vincristine you have a lot of neuropathies.

A phase II study was published in the NEJM early this year. Patients were accrued in a 10 year period. In 10 years they enrolled 51 patients. 65% had mediastinal bulk, 70% has elevated LDH. They received 6 - 8 cycles of the regimen with GF support. The small prints says that 2 patients received RT due to a poor response. The results were compared with 16 patients in a retrospective study form a separate center.

These are the graphs of EFS and OS in the NEJM. The EFS and the outcome are excellent with an EFS of 93% and a OS of 97%. They do not show the numbers at risk. We do not really know how many people has a 10 year follow up or the CI.

In this disease the relapses are exclusively in the first year. There may be late toxicity.

One patient died of AML. Hospitalization occurred during 13% of cycles. The number of patients hospitalized is not reported.

In the JCO they published that they had 74 pts hospitalized. 4 pts had toxicity within 6 weeks from administering ChT. So it is 4 out of 64, which is 3%. They do not report the non hematologic toxicity. They say it was similar to the prior reports. You see this line there is no decline in the ejection fraction.

Many pts get a glucose intolerance due to vincristine. A lot of people need a dose reduction. There is a presumption that giving a CI of adriamycin is safer so you can push the dose. We do not have data to support that. We will see a late toxicity. Most were young patients so they had a dose escalation.

They have to be PMBLC. They must not be grey zone L. At past Lugano when they presented data on grey zone L they said that adjusted dose of EPOCH are not as successful. They can not do it without RT. I am not sure how you can differentiate PMBLCL versus grey zone L.

The other institution that had cases in this paper was stanford. They were consecutive cases acquired in a short period of time. Until few years ago we were treating with R VEACOBP B plus RT routinely. In the last 3 years we treated pts with R ECPOCH. The stanford data were similar to the NCI.

People with SVC syndrome are not to be treated. The pathology is a major issue.

A single institution study should be placed in an appropriate context. No mention is made about fertility with Cyclophosphamide dose escalated. It is too soon to make conclusions about cardiac toxicity. The assumption that patients with this disease who receive RT are prone to second malignancy and cardiac toxicity needs to be substantiated.

There are some contrary findings. There is a similar study of patients receiving third generation ChT R. The EFS is 84% not as good as it was in the NEJM paper.

Our pt receives 6 cycles of R CHOP and had a PR. At the PET CT there is some residual avidity. My oncologist did the wrong thing and gave 2 more cycles of R CHOP and it worked. So we have now a CR on PET.

Should the pt receive RT? For observation there are no randomized data.

The role of RT was evaluated in retrospective series. RT improves the complete response rate. This is a series where CR went from 42% to 95%.

We have retrospective studies which compare pts who receive RT or not after a CR based on an institutional preference. There was an improvement in EFS among the pts who received RT so the EFS was 90% as compared to 75% among the pts treated with ChT alone (CHOP or R CHOP).

We have a study of pts who received a very aggressive ChT including ASCT. About half pts received local RT. When a multivariate analysis was done that included an adjustment for ChT response, stage and other RF, the addition of RT was associated with improvement in PFS. When the analysis was limited to pts who achieved the first line of ChT again pts who received RT did better than those receiving ChT alone.

The conclusions are that there is a small randomized study reporting a good outcome after dose adjusted ECPOCH with low use of RT. There re other studies that do not report EFS as high as shown in the NEJM paper. There is no clear comparative data, no randomized data of R CHOP versus intense ChT. The same level of data suggests a better outcome with IFRT. 30 - 36 Gy is the standard dose.

There is a randomized trial in which the use of RT is the primary study question. Pts who had a CR to ChT are randomized to RT or not. It is an institutional preference as to which ChT regimen is used.

Dose adjusted EPOCH is a very hard regimen. You need to have medical oncologists who are used to give it. It is hard to have a clear cut PMLCBL where R EPOCH can be used. We end up with biopsy proven disease after 6 cycles of R EPOCH. There is no magic in any ChT regimen.

The NCCN guidelines say that if you give R CHOP you need to give RT. You can omit RT if you have a PET CR but we need some randomized data.

When do you give RT for bulky L in stage I II. I give it all the time.

The unfolder trial randomized pts to R CHOP alone or R CHOP with RT on site of bulky and extra nodal disease. The no RT arm was closed at a interim analysis because the EFS was going to be better with combined modality.

Bony involvement at Lugano was statistically significant for DFS and OS.

This is a 13 year old girl with left inguinal adenopathy. They began to grow. Biopsy showed L.

Diagnosis: nodular LP hodgkin. LP cells. RS cells.

PET CT. Excisional biopsy. Progressive transformation of germinal centers.

She has stage I nodular LP.

58% IF 25 - 30 Gy.

It is hard to give pelvic RT to a 13 year old pt for fertility impair. ChT alone is a reasonable option.

ABVD does not work very well in this case. R CHOP is better.

The pt was places on a prospective trial seeking to clarify ChT and RT in nodular LP. As the inguinal node was resected the protocol for this pt was observation.

The concept of this protocol was based largely on reports form europe. They had 58 children with limited stage LP hodgkin. 88% had complete resection with surgery. OS was 100%. PFS was 57% at 4 years.

3 years later the pt had a LN in the left inguinal area. A PET CT showed disease. An excisional biopsy showed recurrence.

Oophoropexy plus IF received most consent.

Among the pts who relapsed the next step in the protocol was 3 cycles of AVPC. If a pt does not get CR he receives RT 20 Gy.

She received ChT alone.

There is a german study about R alone in stage I with good early results.

We use MRI simulation. 

Lady radiotherapist: in the oesophagus you have to worry particuarly at the GE junction.

At the Moffit we put endoscopically fiducial markers, superior and inferior to the gross disease.

Meredith: Siewert classification. Any tumor within 5 cm from the GE junction should be treated as an oesophageal cancer.

Lady RT: case 2. It is a patient 60 yo with chronic reflux and Barrets. We staged the patient as T2 N0 by US.

The patient had pCR after ChT.

My case is a OP case. It is a T2 N1 SCC of the anterior tonsillar pillar. This is the palate and you see the right side of the uvula here. It is an exophytic lesion. The center of it is in the anterior tonsillar pillar. It involves the lateral 1/3 of the soft palate. At CT we have 1 enlarged LN at the level 2a, JD node, at the level of hyoid bone. This tumor was stained positive for HPV. The patient is a non smoker, that is less than 10 pack year.

The question is which is the primary treatment, primary surgery or RT with or without ChT.

Tha majority of the audience voted for primary RT. I am surprised as the indications of the american surgical society are for a surgical approach.

Our standard at the university of florida is primary RT. We do not see a marginal advantage of adding ChT in this T1 – T2 low volume N0 patient so we treat this people with RT alone. We are now engaged in a deintensification protocol but the treatmentis 70 Gy at high risk CTV. We use the RTOG protocol with 56 Gy at 1.6 Gy per F to the elective regions. In this case we elected to treat the contralateral level 2 – 4 nodes. For HPV cancer the range of RT dose is 66 – 70 Gy. We are engaged in deintensification protocol with 60 Gy plus weekly P.

The patient was 58 year old with no major comorbidities.

If the patient is HPV negative would you do radiation alone?

In case of HPV negative or smoker or multiple nodes we add ChT. We do Cisplatin weekly 30 mg per ms. It is considered wimpy and it is not toxicity free. Anyway it is a very tolerated program. It gives the opportunity to stop it quicly if toxicity is developing.

You may work in an institution where the surgeon pushes for TORS. For stage III TC the LC control probability would be the same for radiation and TORS. The main issue in this case is the significant involvement of the palate. I would ask the surgeons if they suggest TORS in such a case. If there is involvement of the palate what would the surgeon expect form the functional deficit that results from resection. This involvement of the palate is a strong argument for RT against TORS.

This patient at Dana Farber would receive chemo RT.

Would you treat the contralateral nodes.

I would treat them mainy due to the significant involvement of the palate. If there is no involvement I would not treat the contralateral neck.

This case is on the border line as only the lateral third of the palate is involved. I would treat the contralateral nodes.

The pattern of the lymphatic drainage of the palat is siilar to that of the tongue. Small lateralized lesions do not have contralateral lymphatic drainage but deeper ones do. These lesions do not need to go to the midline to get to the contralateral lymphatics. Deep tongue cancers put at risk the contralateral neck. The drainage of the palate is similar to the tongue.

Do you think that the contralateral neck can be salvaged with an operation later. From the tongue data the risk of dying from contralateral neck disease is very small. Less than 2% of these patient will have a salvage neck dissection.

I think that we are overtreating the contralateral neck in this patient. The risk of contralateral neck failures is less than 10% in these patients. We put the patient at a life long morbidity by treating the contralateral neck.

In our data the salvage rate is almost zero.

It is a very well lateralized small tonsil cancer but it is a N2b. Do you treat the contralateral side or not.

If it is a bulky N2b I would treat it. If it is a small N2b. If you go to the Toronto and the Vancouver data a very small number of patients had significant N3 disease. The question is can we compare our IMRT HPV data to the Toronto data. There are 2 confounding issues. One is in Toronto when they treat the neck they use a wedge pair with an exit dose of 20 Gy to the contralateral neck. Now with IMRT the dose is much lower. Secondly patients with HPV related cancer have more extended LN mets compared with old series. So the risk of contralateral neck involvement may be higher in HPV cancer.

Yesterday we heard data from Rotterdam where they treated early tonsil cancer with IMRT without treating contralateral neck. Patients did very well. They included 46 patients with palate cancer. One had a contralateral neck recurrence.

The contralateral neck should exclude level 1b.

Would you do a PET to determine the need to treat the contralateral neck. I do not use PET except for looking for distant mets. I do not use it for contouring at all.

If PET is negative in the contralateral neck would you not treat it.

On PET we do not see anything less than 3 mm.

Woud you accelerate the RT dose program. I do always. I do RT in 6 days with one day BID.

Second case: 55 year old woman. Otalgia, dysphagia and sore throat. She had a tumor in the right posterior pharyngeal wall extending to the level of the soft palate. From the soft palate to the adenoid region with possible surrounding sub mucosal extension. She was found to have a 8 cm mass, fixed to the pre – vertebral muscles. She has a history if hypertension. She is a smoker, 30 pack year, she recently quit. We were not checking HPV status on our patients at that time. Stage is T4 N0 M0. 

The question for you is how would you treat this patient that has locally advanced HN cancer. Surgery followed by radiation or CRT, chemo RT with bolus Cisplatinum q 3 weeks and then RT, induction ChT with D C 5FU for 3 cycles followed by concurrent CRT, weekly carboplatinum and paclitaxel with daily RT.

58% voted for CRT with bolus cisplatinum, a third would use induction ChT with TPF followed by CRT, 10% would not use cisplatinum here, a minority would operate. 

In Boston we gave this pt a TPF followed by CRT. She completed ChT in april 2003. At that time we were not using IMRT. She was treated with conventional radiation, dose of 70 Gy and then weekly carpoplatinum. She had a CR. 

She was followed routinely over 10 years with no recurrence, then in june 2012 she developed right otalgia and sore throat. She had a leukoplachia lesion to the right tonsil that is firm to palpation and is confined to the tonsil. It does not extend to the palate or tongue base. She has no trismus. She has fibrosis in the neck. She does have a CT scan which confirms a small tonsillar lesion (8 mm) with no neck adenopathy. We staged it as a T1 N0.

How would you treat this pt in your practice. Would you do a TORS. Would you give radiation to the tonsil and the ipsilateral neck. Would you give RT to the tonsil only. Would you do TORS plus neck dissection. 

51% of the audience would operate. 38% would operate and at the same time do a neck dissection. 

We decided to treat this pt with TORS. On final pathology she has a 2.2 cm mass. Margin is negative. There is no LVI and no PNI. She is a pT2 N0. We operated only on the primary and not on the neck. HPV status is negative by p16 and ESH. 

What would you do right now for this woman who is now 64. Would you do a bigger operation to get a bigger margin plus a ND, would you do just a ND now, would you do radiation to the primary site, primary site and neck, would you give this woman concurrent CRT.

We have a parity here for 1 and 2. Some of you would take this pt back to the OR for more surgery, including primary and neck. 32% would do an ipsilateral ND. We did a ND only. She was pN0. 

This is an interesting case of second primary tumor 10 years after sequential therapy. I want to show some more slides. We treated this woman with this regimen. This is the 324 study which compared 2 induction ChT regimens (D, P, 5FU - P, 5FU) followed by carboplatinum - radiation. 

This study included patients with OP primary (more than 50%) in good PS who entered the study because they were unresectable, or they had low surgical cure or they were included for organ preservation. This study essentially showed that if you add D to P - 5FU you do better than P - 5FU, you improve survival and PFS. 

We published last year the 5 year update of this study which continue to show that TPF is superior to PF with an improvement in survival. There are 2 other studies showing also that TPF is better than PF. So the message is that if you use induction ChT you should be using TPF; that is the standard induction ChT regimen. 

The bigger question in treating these pts is what is the role of in induction as a modality for treatment. You need induction ChT for those pts to improve survival. For those of you who went to ASCO this year there were 2 presentations comparing sequential to concurrent CRT for HN cancer (locally advanced disease). Both of these studies were not accounted for HPV (there was no stratification for HPV). Both of these studies did not complete the planned accrual and were both underpowered. They both did not show any advantage of one regimen versus the other. There were no differences between sequential and concurrent CRT. 

This is the DECIDE trial that has a particular concurrent CRT regimen. This is a BID radiation with D, 5FU. Like our study, the DECIDE study showed no advantage for induction ChT in these pts. 

These are some scenarios I would use to consider induction ChT for my pts. We can debate this. 

This pt did very well, she responded well to treatment and has a good QOL. I think this pt has 2 options for treatment, concurrent CRT and sequential CRT. To me these 2 options are completely appropriate for  a pt with T4 OP cancer. I would agree that many people would consider concurrent CRT the level 1 evidence and standard of care. I think we have enough evidence with phase III studies with sequential treatment which is also an effective modality for treatment Unfortunatey DECIDE ans PARADIGM were underpowered to answer this important question. I would consider sequential CRT to be an appropriate therapy for pts like this one.

We have to be careful about whom we select for this approach, about PS and comorbidity. TPF regimen has its own side effects. But in carefully selected pts with PS 0 - 1, those toxicities are manageable. IN my opinion this pt would have these 2 options for treatment, they are both appropriate, they were appropriate in 2002, they remain appropriate today. 

Would you do induction in your institution in this pt.

No. This is a reirradiation case. 

What about the first scenario.

You mentioned the most important ChT issue trials for 10 years or so in 2 slides. I think that the role of neoadjuvant ChT is in a pt that is too bad off to start RT, meaning that the only pts that I treat with neoadjuvant ChT are the people that about to die of malnutrition and can not lay down on the table. 

The best treatment is concurrent CRT with accelerated RT. If this T4 pt was such that, they are unable to handle their secretion. They need a feeding tube tomorrow. They were metabolically out of control. We need weeks of management. I would talk with my medical oncologist and he unhappily agrees to start neoadjuvant ChT. Otherwise we would treat this pt with accelerated 2 weeks RT with concurrent ChT. 

The other aspect of the case was should recurrence be treated with surgery or reirradiation or reirradation plus ChT The audience showed surgery in those pts who are resectable at recurrence. 

Would you do any different in a pt who is resectable or is resection likely to result in significant functional deficit so sometimes we decide differently in such patients. 

This reirradiation case is a great case as it represents what we are challenged with. In our weekly tumor conference we have 10 pts and at least 3 ones are reirradiation questions. If you take all the publications and you see what is the value of reirradiating a second primary in HN cancer with high dose field like this case, there are many papers encouraging reirradiation. My opinion is that they are all meaningless Reirradiation is a disaster. It causes complications. We treat highly conformal only to the GTV plus a cm. We do not deliver any elective nodal treatment. We are doing a publication where the failure rate in the elective nodes in people previously irradiated is low. I reirradiated one pt and he had every possible late long term toxicity (cranial nerve deficit, mandibular necrosis) but he was cured from reirradiation. In this case I would have done only surgery. 

In you reirradiation protocol is there any role for BT.

In the literature if you look at BT for reirradiation the risk of soft tissue damage is higher than in EBRT. There are new technologies like hypoF, with 5 or 6 fractions, Assuming that larger F will overcome the resistance to radiation. The biological risk of complications may be higher even if you are very tight to the tumor. So far the data that have been published on hypoF do not suggest any better local control than others. I would like to add that in our experience we treated gross disease with close margins. All loco regional recurrences were within the gross tumor. This is because the rate of local control is so low so you do not have the opportunity to see loco regional recurrence. You can have 5 year survival of 30%. The risk of complications is 30%. Mucosal complications are the largest ones. Carotid blow out can be due to tumor progression. 

Following the second primary resection the margin were clear. So why did we do ipsilateral ND. It was  T2 and we thought it was a T1. 

The neck was addressed previously by irradiation but as new cancer arose the neck is again at risk. The highest risk is in the previously dissected neck where for sure any recurrence will be non salvageable by surgery. In this case the ipsilateral neck was not dissected before so ipsilateral ND should be tee good option now. 

Given an excellent response to induction TPF, would you treat a smaller volume or to a lower dose of radiation. As a medical oncologist I would tell you no. We do not modify how we give radiation base on how the pt responds to induction. That too is a research question. There are trials like the ECOG study, which is completed now. In HPV positive pts it asks the question of induction first. If you have a CR or a good PR you get 54 Gy of radiation with ChT but that is a study question. At this stage if you are using induction ChT you should not be giving less or more radiation based on the response. 

I struggle with that in pts that are being managed with induction ChT. I do not change the volume based on the response to induction ChT. I think it is not a satisfying situation. 

This question is parallel to the question what do we do during radiation. We have CBCT, we see the tumor shrinking. Should we shrink the GTV. We shrink the GTV after induction ChT, should we shrink GTV during radiation. 

This is a 33 old female with intermittent recent blurred vision and headache for 2 - 3 weeks. No significant PMH. Left sixth nerve palsy. In radiology we see a large tumor in the nasal cavity and sinuses invading the orbit, invading the dura with extension into the brain. Biopsy showed a sino nasal undifferentiated adenocarcinoma. 

What is the best treatment option in this unresectable case. Steroids started right away. The question is what to do now. 1 - starting ChT cisplatinum - VP16 for 1 - 2 cycles aiming to shrink the tumor to allow better sparing of the optic nerves by irradiation. 2 - ChT may not be fast acting therefore we need to start radiation alone to avoid a higher optic nerve toxicity form CRT. 3 - start CRT. 4 - start CRT concurrent with amifostine which is known to reduce optic nerve toxicity. 

We decided to go concurrently. High dose cisplatin - VP16 q 3 weeks. Concurrent radiation. The CTV1 was the MRI based tumor plus edema in the brain part plus 1.5 cm margins tighter near the optic nerves. PTV was 3 mm extension assuming that every day we do imaging to check set up uncertainties. This extension was tighter near the optic nerves. We started with 2 Gy times 5 using 3D because we had to start right away. In the meantime we planned IMRT and we gave additional 40 Gy to a total of 50 Gy. The plan was to review tumor shrinkage and possibly modify the target after 50 Gy. 

We treated just the primary. The risk of LN mets is about 15% but due to the extensive primary tumor and the feeling that our chance to control it was not that high we decided not to treat the LN profilactically. 

This is the IMRT set up. 

This is the dose distribution. 

After 50 Gy we did MRI which showed significant regression of the GTV. The optic nerves which previously were pushed to the side by the tumor extending to the orbit are now back straight. The tumor is likely away from the optic nerve. It is much easier now to spare the optic nerves if we continue with the new GTV. 

Here is the question. If the tumor shrinks substantially at mid therapy, should the primary GTV1 routinely be modified. Shall we do a new IMRT plan sparing more tissue. Or modification of the GTV and a new planning should not usually be done. 

We decided to shrink. The cumulative dose is 70 Gy, while 54 Gy treat the old GTV. 

Should we treated this pt with protons. 1- protons would cover the target and spare the optic nerve better than IMRT. 2 - it is not necessarily so. 

SNAC. If resectable (no involvement of the brain), cranio facial resection followed by adjuvant CRT or CRT followed by resection are the standard. If non resectable like this case either ChT followed by CRT or CRT The problem is that we do not have data. In the literature the typical series is less than 10 pts. With larger series of 16 - 17 pts no consistent treatment. No conclusions can be done by the literature. 

What about doses. In U Florida data 2 of 4 pts receiving 70 Gy concurrent with ChT were locally controlled. 50% of pts receiving 70 Gy are NED. In australia the results are stronger. 100% of pts receiving 60 Gy concurrent with cisplatin are NED. This is what we have. So 70 Gy control 50%, 60 Gy control 100%. This is a reflection of the lack of data. 

If you look at the treatment of sino nasal tumors SNAC is in the middle. Esthesioneuroblastoma is much better. Neuroendocrine tumors and SNAC are doing about the same. Small cell cancer of sino nasal cavities to the worst. 

For small tumors LN  should be treated if you have good chance of local control. 

What about shrinkage of tumor following either ChT or radiation. 

Some canadian medical oncologists introduced induction ChT during the late 80s when induction ChT was really hard. When we get a CR we get 1 or 2 logs out of 9. This is the argument why neoadjuvant ChT in the 80s did not translated into better survival even though we saw a CR. We have some subclinical disease. This as far as reducing GTV if we have response to induction ChT. We should not. 

The same happens during radiation. We know that tumor shrinks during radiation and so LN. Now we see it at CBCT. At 50 Gy we do not see the edges of the cancer any more but we killed 1 or 2 logs out of 9. 

In this case there is benefit to shrink the GTV which is getting off the optic nerve. In general my suggestion is do not shrink the GTV whether after induction ChT or during radiation. 

Protons. Most of the studies comparing IMRT and protons are done in the same institution like U Florida. The report are that protons are better. There is conflict of interest. 

We made a poster with 2 institutions (I am not speaking about IMPT which is a different story). Protons have no advantage over good IMRT for base of skull. 

We will publish a poster for next ASTRO. My proton colleagues in my institution will disagree with you. There are small changer in how you contour the target. It is difficult to say what is an important dosimetric difference. There are always parts of the DVH that look better with one technique versus another especially with heavy particles. There is no question that if you want to find a positive result with proton you always can because there is nothing like protons when it comes to low dose bath.