martedì 14 gennaio 2014

HN cases.

First case. This is a case of a stage T4a SCC of the larynx. This is a 55 year old man with SCC of supraglottic larynx. On CT we see a tumor of the right side of the epiglottis. This is at the level of the false vocal cords. This is the aritenoid cartilage at the level of the arytenoid notch. The arrow is pointing to an area of tumor where there is extra laryngeal spread along the path where the superior laryngeal nerve enters the larynx. This would be the border of the gross tumor on this specimen so you can see the extra laryngeal spread. This is the outline of the tumor involving the entire false vocal cord and extending posteriorly here. This is the inferior level of the tumor and it occupies the entire emi larynx close to the aritenoid cartilage.

We staged this pt T4a (extra laryngeal spread). There was no direct cartilage invasion, no sub glottic spread of tumor on the CT. The pt was staged N2b because there were 2 radiographycally positive LN in the ipsilateral neck. They were 2 cm pathologically appearing LN confined at levels 2 and 3 on right side. The RP nodes were radiographycally negative.

The pt needs his voice to function. The tumor was high risk HPV positive. He is a smoker with 15 pack year. Primary tumor volume was 20 cc.

What primary treatment do you recommend.

What do you think the HPV status mean.

My opinion is that it is not an important prognostic variable outside the OP. We do not make any clinical decision on p16 HPV status outside the OP.

A pt like this tests the limits of organ preservation. He has a fixed vocal cord and a hoarse voice.

Traditionally we would treat him with a total laryngectomy. We would hesitate a little as he needs his voice. The best chance to be cures is total laryngectomy and bilateral ND.

I would not go for surgery as my first option. I would attempt organ preservation.

Option 2 is neoadjuvant ChT. How does it fit in the evidenced based data that you pointed out. Why would you do 2 versus 3 for example.

For larynx cancer there is no information that NA ChT is an appropriate approach. RTOG 91 11 was presented 2 years ago. It showed an advantage for concurrent CRT in terms of larynx preservation. There was no advantage in OS for all the 3 arms (the 3rd arm was radiation only).

This year we saw the 10 year update of this trial. It confirm larynx preservation for CRT but many pts are dying of unknown reasons or toxicity. When you look at the survival curve on that paper there is a 11% survival advantage for induction ChT. P is not statistically significant. Anyway 11% is a significant number. 91 11 was a trial where many pts had an intermediate stage disease (mostly T3). Even in a T3 pt population you have a study where the curve shows an advantage of induction ChT. TPF is superior to PF.

If you look at the NCCN guidelines there is a lot of controversy with induction in the OP. In larynx in particular the NCCN guidelines put an equal importance for induction ChT and concurrent CRT.

Regardless of the options you choose for this case, which T4 larynx cancer pts you think are eligible for a larynx preservation treatment whatever the larynx preservation treatment is (CRT, induction ChT).

These are pts where the larynx function is so bad because the larynx is destroyed. It is not worth trying to preserve the larynx. Laryngectomy will be clean. The pt will have a stoma. Voice can be restored. In this case the pt has a hoarse voice but we do not heard that he aspirates a lot. In this case it is worth trying to preserve the larynx. Cases in which the pt need treacheostomy are at risk of obstruction and need aspiration; here larynx preservation is not worth.

The minority of the audience would manage the pt with laryngectomy. The second choice is larynx preservation with a NA approach. Almost half of the audience would recommend larynx preservation with concurrent CRT.

At U Florida we manage these pts with laryngectomy.

We strongly recommended total laryngectomy with adjuvant treatment. We all need to recognize that we need another tool besides tumor stage to choose winner and looser pts for larynx preservation. At U Florida we focused on this tool which is primary tumor volume. The break point is 12 cc. What you see is that the success of larynx preservation in tumors greater than 12 cc is 44%. This pt is way above 12 cc. The chance that our treatment would be successful is very low. We do not believe the conclusions of 91 11 trial.

The option of induction ChT followed by CRT that was done in the intergroup study was not simply induction ChT followed by CRT. It was induction and then assessment of response. Only pts who responded with tumor shrinkage went on CRT. Those who did not went to surgery. This is an important distinction. The VA study (3 cycles of PF and those who responded went to radiation alone) found that pts with T4 did not do well. But this was radiation alone. When we do CRT we achieve better results in T4. Radiation and ChT double the volume of cancer that can be cured.

We can see if there is PR after 3 cycles of induction. At U Michigan we give 1 cycle of ChT. If there is PR the pt goes to CRT as he shows intrinsic sensitivity to treatment. Using this approach the local control of T4 is equal to T3. Those pts who do not respond after 1 cycle of ChT go to surgery.

Even with induction ChT pts like this would have a long term larynx preservation rate of 60 - 65%.

Salvage surgery is done immediately if CR is not achieved or if there is local recurrence. We can have pts whose larynx is preserved (those who are more sensitive to the treatment). The important thing is not to loose those who do not achieve a PR or those who have a local recurrence.

At NCI statistics only for one cancer the survival is going down: larynx cancer. The reason is that we are treating poor prognosis pts with larynx preservation. We are paying a price in terms o survival and complications.

When we have good genetic information and molecular information we can drive therapy much better.

Second case. I choose a case of NPC. I am asked how do we manage NPC in terms of ChT. This a 45 year old male. He was born in China and then came to US. He presented few months ago with tinnitus and sensation of right ear blockage. A large mass in the NP was identified more on the right. He had no neck adenopathy. We did MRI and PET. Biopsy showed NPC non cheratinizing EBV positive. We staged it as a T4 N0.

How would you treat this pt. 1 - concurrent CRT with bolus cisplatinum. 2 - RT alone. 3 - induction ChT with docetaxel platinum 5FU. 4- surgery. 5 - concurrent bio RT with Cx and radiation.

What is the standard of care in this case.

The standard of care is established by al sarraf trial (concurrent high dose cisplatinum q 3 weeks and radiation followed by adjuvant cisplatinum and 5FU). We do not know how many EBV were treated in the al sarraf study. We know that if this pt was caucasian treatment should be as aggressive as possible especially if EBV was negative because in this case he would not do well locally (as local control).

Being EBV positive cancer endemic, he may do quite well with the standard treatment.

I agree that treatment should be concomitant CRT followed by adjuvant ChT as proved by the al sarraf study. Some people are wondering if adjuvant ChT is still important. What would you do at the U Florida.

We gave up the maintenance component of the program over 10 years ago. Without data to prove that it is ok to to that. Anyway our thinking is that toxicity is very high and benefit is low. We have substituted weekly platinum for the US standard of 100 mg/mq. I would use ChT in addition to RT even though it is an unusual case of locally advanced primary without adenopathy of NPC. I would use 70 Gy.

79% of the audience would use concurrent CRT. Only 21% would use induction ChT.

We treated this this pt with concurrent CRT. Cisplatinum q 3 weeks 100 mg/mq as it was used in the al sarraf regimen. All the following are potential side effects.

We treated this pt with concurrent CRT. At 8 weeks he is asymptomatic. He has only a dry mouth and grade 1 fatigue. He is NED. He had a CR.

What would you do right now for this pt. Would you proceed with 3 cycles of ChT with PF as was done in the al sarraf study. Would you stop treatment here. Would you do endoscopy and biopsy of the NP. Would you do a ND. Would you check EBV DNA.

What is the policy at U Michigan.

Our medical oncologist would do adjuvant ChT. Soon there will be a RTOG study that will look at plasma EBV after treatment and evaluate the pts for adjuvant treatment according to EBV titles.

At Beth Israel we would generally treat such a pt with adjuvant ChT but we are increasingly having a discussion with pts. There is growing evidence although not yet randomized studies (omitting the adjuvant ChT may be appropriate). In my way of thinking it is still the standard of care. It does require a discussion. It probably does not add very much to the outcome.

We did not give this pt any further therapy. We stopped after concurrent CRT. The idea of discussing this case has to do with some of the phase III data with the role of adjuvant ChT. NPC has a propensity for distant mets.

There have been 2 paradigms, one is concurrent CRT followed by ChT based on an old SWOG study (al sarraf study from JCO). There is an old study published in 1998 radiation only vs concurrent CRT followed by ChT. The study was stopped early because the results were significantly in favour of the concurrent CRT followed by ChT arm. You can see here the RT arm performed so badly. Even with RT alone right now we do much better. This study established he standard of care in the US for the past 25 years.

The NCCN guidelines reflect that. The recommended treatment for these pts has been concurrent CRT followed by ChT (level 1).

The problem with the al sarraf study is the control arm. It is RT alone which all of us would not do. If in the al sarraf study the control arm was CRT would we have seen better results. These are the studies with sequential or concurrent but all of them used the same control and that is radiation only. They do not help us in answering the question of the role of adjuvant ChT in these pts.

This study was published last year. This is the purpose of presenting this case, to review this study. This study is from China. A large study ore than 500 pts. Concurrent CRT followed by ChT versus concurrent CRT. Mostly IMRT pts treated with weekly ChT. 2D RT or IMRT, almost 50 - 50. Most were males. They were T2 T3 T4 but they had to be N+. The primary endpoint was FFS. For this endpoint there was no difference between the 2 arms. Sequential or concurrent did the same. For OS no difference. Even for distant failure no difference. All the curves favour the induction. This study is a negative study and it does not support the role of adjuvant ChT in these pts. The median follow up is 3 years. No improvement at 2 years. It supports the use of CRT alone. The adjuvant phase did not improve survival.

Based on this study the NCCN have been updated this year to reflect a third option. You still can do the al sarraf regimen. It is still level 1 evidence. It is not the only option. Concurrent CRT is an option for these pts.

What is important is to give cisplatinum. Do not use carboplatinum or taxanes. The role of adjuvant ChT is not put in question because of the study I just showed you. It is not wrong to use the al sarraf regimen. I use it for pts with advanced nodal disease. There is an ongoing study in China that gives adjuvant ChT based on EBV titles.

I have no information to say that we should treat everyone with al sarraf regimen.

Second case. It is a 63 year old female who presented with 3 problems. Right parotid mass (3 cm) with palpable level 2 LN (3 cm, ipsilateral). A PET CT revealed a hypermetabolic lesion in the right parotid with multiple LN at levels 2 and 3. A FNA revealed adenocarcinoma. She underwent 3 surgical procedures. She had 3 simultaneous malignancies (melanoma in situ excised, carcinoma of the breast RT, parotid poorly differentiated salivary duct carcinoma 3.2 cm with positive LN with ECE, negative margins).

How would you manage the parotid cancer. Post operative RT to the right parotid and neck, RT to the right parotid and both necks, CRT, Erbitux RT, surgery alone.

I would do concurrent CRT. Weekly carboplatinum and paclitxel. Often we use Herceptin in HER 2 new positive pts. This one would not be candidate as he is HER 2 negative.

Would answer about treating one or both necks.

This is a myoepithelial tumor. They are rare. We treat these pts with RT without ChT. I would choose option number 1. I do not see an indication to treat the contralateral neck. There are no significant cross over lymphatics form one parotid to the other. When you have such a bulky adenopathy on one side the risk of shunting to all over the places is present. I would do option number 1.

I think this pt is a high risk of recurrence as she has ECE. From a surgical perspective I want to be as aggressive a possible so I would choose option number 3.

I treated this pt with post operative radiation to the parotid and neck. The medical oncologist offered the option of including ChT. It is my preference outside a clinical trial. I treated her with RT to the primary site and to the neck. She completed her treatment in 2010. In april 2011 she a surveillance PET CT that showed a hypermetabolic LN in the contralateral neck (which I did not treat). A FNA revealed adenocarcinoma consistent with parotid cancer (not breast).

I first want to show what the audience said. There was sympathy for using ChT. Most of radiation oncologist in the audience will favour ipsilateral treatment. Only a few of them a contralateral treatment. Now you see what happens to this pt. This is a rare contralateral neck recurrence.

How would you manage the pt. The choices are ChT, concomitant CRT, surgery plus post operative RT, radiation alone, surgical salvage.

I recommend ND followed by RT.

I have never seen a case like this. I always treated ipsilateral neck in such cases. The risk of both regional recurrence and met is overwhelmingly higher the risk of recurrence in the contralateral neck. I would do ND. I assume it will be a single node completely excised. I would check for HER 2 new in the parotid specimen. Ductal parotid carcinoma looks like breast cancer under the microscope. I would choose surgery minus post operative RT.

The pt had a left neck surgery. Pathology revealed adenocarcinoma in one of 26 LN. There was no ECE. It was a salivary cancer.

Any more treatment for this patient now.

I would add adjuvant therapy. ND has 3 - 5% of false negative rate. Now I would say post operative RT.

90% of the audience agree with ND and post operative RT. I spared the very upper part of this woman neck. She recurred in the upper part of her neck 6 months later. She was resected and we gave intraoperative RT. Then I have some additional EBRT. This was done with cisplatin. Recently she developed cutaneous nodules in the lower part of the neck and the upper part of the chest.

Not treating the contralateral neck is evidence based. In a paper I wrote there was not a single instance of contralateral neck failure. There is also a paper from MD anderson about not treating the contralateral neck. In terms of post operative RT there are no randomized trial to tell you that post op RT has a level of proof. But you have a better local control if you add post op RT. This statement is made stronger by the fact that those who got surgery plus RT had more adverse prognostic factors.

In this paper pts with stage III and IV disease and N+ had a better outcome with post op RT.

We published a paper where heavily pre treated pts received surgery, IORT, flap reconstruction, more CRT. We got a good in field control, DFS, OS. This was a very heterogeneous group of pts (UCSF).

The pt should have had a comprehensive ND.

Next case. This is a young woman non smoker. Clinical stage T1 N0. SCC of the mid lateral oral tongue. We resected it. Pathology showed a tumor with depth of invasion 4 mm, negative margins no PNI or LVI. Moderately differentiated.

What about adjuvant therapy: a - as the tumor is 4 mm no further therapy; b - as depth is 4 mm we end the pt back to the surgeon for ND; c - as depth is 4 mm we go to radiation to the ipsilateral neck; as oral cancer has a high risk of recurrence in younger pts, therefore radiation to the primary site and ipsilateral neck.

A comment about age as an emotional prognostic factor versus a real prognostic factor.

A 29 year old female should not get a SCC of the tongue. This pt is extremely concerning. We do not know what to do with this pt. We recommend ND because of the depth of invasion. I think that the issue of CRT is open to discussion.

One concept is to do a ND. If it were negative than you can argue that the primary site was properly managed. If ND is clear I will then do only watchful waiting.

The indication for ND in OC cancer is depth of invasion more than 2 mm. This is 4 mm. The colleague put this lesion at the midline (midlateral), so it is more than 1 cm from midline. So it is a lateralized lesion so it needs only an ipsilateral neck treatment. We would do that. A neck dissection is less morbid than RT to involving the OC and neck. This pt has not an indication for RT in the primary site so we take the indication for ipsilateral ND. No RT unless there are the classic indications in a ND.

The majority of the audience would send the pt to the surgeon. 24% would say no further therapy. No one recommended RT to the ispsilateral neck instead of surgery.

In the 80s you published a series with 100% control with radiation in clinically negative neck.

The question is which treatment is least toxic. 1.05

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