Altered Fractionation
Invite everybody to comment on altered fractionation in head and neck cancer- Is it going to stay or die in the hands of chemoradiation ?
Altered Fractionation
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» Altered Fractionation
It may have died but I suspect with the advent of IMRT it will have a renaissance in the form of integrated boost treatments. Infact the very conformality of IMRT lends itself to application in altered fractionation regimens like concomitant boost / accelerated hyperfraction very nicely if we can just overcome the logistical problems. However the mucosal toxicity profile will proabably remain invariant unless we find out a way to reduce the uncertainity in segmentation.
That said I feel IMRT will pave the way for the final integration of altered fractionation with concurrent chemotherapy in future
Srinivas
Altered fractionation is not always an alternative to chemorads. Its role in current practice is often in patients who are not suitable for chemo in some form or other. Sometimes even in patients when you consider the need for chemo borderline eg. a relatively small T3N0 primary.
I agree with Santam that to a certain extent - schedules like concomitant boost can be incorporated into IMRT schedules although I am not very sure that this has led to better outcomes (please correct me if I am worng). I also feel that IMRT does not actually allow a concomitant boost -it is really a hypofractionation wrongly named - and quite different from a concomitant boost with less than 2 gy per delivered fraction.
Treatments like the traditional concomitant boost have not really held up to its promise in the setting of concurrent chemorads (as in the results of RTOG 0129) that you saw in ASTRO.
In the setting of cetuximab - we know however that it seems to help! Interesting isn't it?
Will altered fractionation RT alone be considered as a standard de-escalation protocol in HPV + oropharynx? You never know.
Personally I don't think altered fractionation will die - not in the hands of dedicated HN rad oncs - but its role on paper and in guidelines is uncertain.
I should have made myself clearer. I meant concomitant boost with doses less than 2 Gy treating twice a day as per the schedule or hyperfractionation. I feel it will definately give a better dosimetric profile as compared to conventionally delivered CB/HypRT. SIB is a form of hypofractionation/accelerated fractionation.
To be more explicit where we deliver an IMRT plan with 2.2 Gy to primary and 1.4 - 1.6 Gy to cord (even less to parotid) we will have greater sparing of the cord if our delivered dose per fraction is less than 2 Gy. However I feel mucosal toxicity will be an area of concern as IMRT does expose the entire oral cavity to low doses and tolerance to such doses in twice daily schedules can be questionable. In conventional conformal treatments however this part of mucosa gets spared. Interestingly many series do report less mucosal toxicity than with conventional RT when using IMRT. What is the experience of the house?
You are right about the outcomes part Indranil da but I feel we have not really explored altered fractionation with IMRT to be sure. I will definately like to work on a protocol on this aspect once I get to the consultant level.
One question for you Indranil da the only report of RTOG 0129 I am aware of is that in ASTRO last year focussing on the toxicity part and the one in ASCO focussing on HPV vs survival. Did they have anything on the outcomes too?
Dear everybody
If we talk about the evidence, the real benefit of altered fractionation is in stage III patients, younger and fitter patients(MARCH meta analysis, forest plot). This is the same subgroup of patients where chemorads works best as well. Unfortunately there is no head on comparison between altered fractionation in strict sense vs chemorad with conventional fractionation (ofcourse except the ORO trial which is actually a poor comparison). Unless there is a head on comparison, between these modalities there will be never a consensus and the chemorad is going to have an upper hand as it has a superior biological rationale. coming to T3 N0M0, there may be evidence to suggest that the chemo may have less benefit, but there is no evidence for a great benefit with altered fractionation as well. These patients probably do well even with conventional radiotherapy.
HPV + oro tumors are again well behaved relatively, so if there is no need for intensification with chemo, it may also be futile to intensify it by altered fractionation.
Yes I agree all the trials with altered fractiona are with conventionally designed portals and not with IMRT, and we need trials with IMRT. All the best to Santam on that front. forget all the hyper protocols santam , as they arent practical.
SIB is convinience, but you have to believe that with fraction size of 2.2 you have really got to restrict the volume recieving this fractionation or else you will end up having higher toxicity.
Guys, great discussion, I want to know how many of you really use altered fractionation in real practice ? Here we don't even talk about it, all depends on how strong the Radiation Oncology team is, probably then you can have a trial, remember Asian's can do HN trials in a very short time given the patient number that we see. Srinivas which ORO trial ? Can you please send us the pubmed link.
We are practising concurrent chemoradiation where radiation is given as simultaneous boost.These most of our patient treated are nasopharyngeal carcinoma.
Presently we are running a trial in lung using simultaneous boost .if interested i can send u all the trial details.
1. Bourhis et al. Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis Lancet 2006; 368: 843–54.
2. C Srinivas et al. Altered fractionated radiotherapy in head and neck cancer. Lancet 2006 ;368:1867.
3. Olmi et al. LOCOREGIONALLY ADVANCED CARCINOMA OF THE OROPHARYNX: CONVENTIONAL RADIOTHERAPY VS. ACCELERATED HYPERFRACTIONATED RADIOTHERAPY VS. CONCOMITANT RADIOTHERAPY AND CHEMOTHERAPY—A MULTICENTER RANDOMIZED TRIAL. Int. J. ROBP;55, No. 1, pp. 78–92, 2003.
Sorry for not putting refences. I could not found option for attachment.
Nikhilesh
We use altered fractionation all the time in PMH. We use DAHANCA fractionation (6/wk with one BID instead of 6 days) in the majority of patients who are not good chemo candidates. Unlike most of the med oncs in India, the med oncs here are a bit on the conservative side and many patients do not get chemo. The other fractionation schedule we use is called HARDWINS (http://www.pubmed.gov/18342965) - it is 64Gy/40fr/4wks (i.e.1.6Gy BID). That is an accelerated hyperfractionated regimen pioneered in PMH designed to complete RT in 4 wks before accelerated repopulation starts. In the original protocol, neck surgery was an integral part of the treatment with the neck always receiving a microscopic dose regardless of positivity. It is now practiced in a modified format with radical doses to the neck too in a selected cohort of patients not fit for chemo and essentially N1/small volume N2 disease.
Some elderly patients with T1-2/N0-1 disease also get 60Gy/25Fr.
In terms of my training I feel fortunate because I have seen a very wide spectrum of fractionation schedules in HN during my entire training. Earlier I had a considerable exposure to concomitant boost in PGI (http://www.pubmed.gov/18343310). I would always attempt acceleration whenever chemo is not indicated or possible - i.e. in any early stage HN ca as well. I feel 70gy in 7 weeks without chemo is a pretty lame fractionation schedule. I would not like to be a slave of evidence here. If you can finish it sooner - do it.
Thanks for update Srinivas, Indranil and Rajesh. I agree we should use altered fractionation in routine practice for suitable cases. Recently we had an in-operable anaplastic thyroid ca patient with tracheostomy. I wanted to give 60gy @ 1.5 Gy B.i.D (40 #) over 4 weeks, which works well but we ended up doing 70gy/33# IMRT with hardly any response.
Rajesh — please send me the lung protocol, I see Lung ca on reviews, it will be nice to see what you guys are trying to do.
Dear Indranil
Can you clarify weather 6 day/wk fractionation is being practised conventionally or with IMRT? The HARDWINS study has shown high number of grade III mucositis as well as persistent dysphagia. In Tata I have seen 32/8#, 55/16#, 60/24#. I think these hypo fractionation works well if you can limit the volumes.
Srinivas
IMRT. Every HN patient here is treated with IMRT with daily kv conebeams, even T1 glottic. I agree that volumes make a difference in hypofractionation.
Dear all,
Head and neck squamous carcinoma.
concurrent chemo radiation benefits,treatment time reduction benefits,more than 2 gy per fraction benefits.
only thing what we are not sure is about subclinical disease.we consider 50 gy is enough.not much evidence.
So what we here think is that concurrent chemoradiation with simultaneous boost with tumor gettiing more dose per day and reducing over all treatment time although subclinical disease get 50 gy in protracted way.if dose per fracton is reduced to area of subclinical disease and normal tissue,late toxicity is less.Acute toxicity depends on volume of GTV.
As of now in nasopharyngeal carcinoma although most are undifferentiated local control is same or better .3 year data.Dr Jay Lu has done this work here along with his friends in china.
What is being done in T1 glottic IMRT? Carotid sparing / Dose homogenization / Arytenoid sparing? What are the dose constraints you keep in this case? Do illuminate on this interesting topic. Somehow I cud never convince my consultant for this here but may be for good as we dont have CBCT :-)
Santam
To be frank I don't think they use any specific carotid constraints here yet. Although that's where its ultimately leading to. My advice is not to do it unless you have good quality soft-tissue matching with CBCT - bone matching on vertebrae is worse than no matching in terms of craniocaudal uncertainty. Be very careful if you attempt it. Theoretically - you can do partial larynx irradiation and certainly give carotid constraints. I am sure that in the future this will become a standard with IGRT.
No question of that arises here … I get drubbed for doing it for maxilla he he
Am I missing something? Carotid sparing, sub-site irradiation in the larynx??
1. Have I missed some evidence about carotid problems after RT? reference please!
2. The larynx moves +-2.0cm when swallowing, how are you going to provide an arytenoid sparing approach without introducing into the discussion techniques such as swallowing-gating? Or is there a clever way to fix the larynx? Certainly telling patients NOT to swallow only makes it happen more often!
Dr Andrew,
My primary intention form the query was to learn. After all dosimetric studies do exist about carotid sparing but I was not aware of anyone doing it clinically. When Indranil told their center does I was immediately interested to learn about the how and why for this specific subsite. My queries stemmed from the fact the articles dealing with IMRT mainly focus on these issues.
Now I am not aware of much morbidity with conventional RT in early glottic carcinomas in our institution. So while I will not be using this technique myself it will be interesting to know the rationale of treatment in those who do use it and how they go about doing it in real practice.
Concerning the question about carotid sparing some data does exist that RT increases the risk CVA[1] as compared to non-irradiated controls, but till date in my institution I have seen patients dying from cancer mostly and rarely from CVA. Of course fact remains that our follow-up is not that good. T1 glottic cancer patients however do come for follow-up and have excellent control and QOL overall.
After reading this thread however I came across this recent paper by Dr Rosenthal in IJROBP[2] which deals with this issue. The authors have given a blanket statement in the discussion that competing causes of morbidity may be important after 5 years follow-up however no citations to support the statement.
Coming to "laryngeal gating" I am not sure if it even exists and if it does how it can be implemented
Indranil,
Dont worry I am not doing it or planning to do it. If practicing in India I will be having my handsful with complex head and neck to really waste time with IMRT in T1 glottic larynx something that can be reliably cured with a simple 2 field arrangement
Bibliography
Just to refresh this post. Altered fractionation (accelerated or pure hyperfractionation) has conclusively shown to improve the loco-regional control. This is evident from various trials. But one big question. Why doesn't this improved loco-regional control translate into improved overall survival?
Reality is merely a persistent illusion
With reference to T1 Ca glottis, we at RCC Tvm, have been using the old Manchester schedule… 52.5 Gy/15#/3wks. The local control rate is good with 5yr DFS of 94%. They do complain of hoarseness on excessive straining, otherwise they have good quality of voice. With image guidance, i guess we can bring down the irradiated volume a lot, and with arytenoid sparing in the chosen patients, the quality of voice can be preserved.
Dear all,
1.Do we need to take a planning ct scan again for planning the concommitant boost?
2.Since the 1.5 gy per fraction for the last 12 fractions in a concomittant boost is not always well tolerated along with the daily 1.8 gy per fraction to the larger portal, can 1.2 gy per fraction be used as the boost?
3.Can the concommitant boost be used in brain tumors as well?
Arun,
There were oral presentations on MR guidance to reduce the margins. I dont know if that got published. I will request srinivas to comment, he presented tmh data (oral presentation) at ASTRO 2008.
According to the data I presented at ASTRO 2008, the locoregional control was better in patients who recieved hypofractionated RT (>2.5Gy/#). The data analysed three differenr fractionations- 55Gy/16#, 60Gy/24# and 60-66Gy/30-33#. the toxicity data was same in most aspects but the rate of persistent edema was higher in patients with hypofractionation. The persistent edema was defined as edema persisting for more than 12 weeks. Although I must admit there were limitations in documenting toxicity as in any other retrospective study (esepcially if u have to dig data more than 25 years old). the voice quality as expected was not analysed. So no comments can be made on that.
Perception may not be reality. The patients who have events like cardiac including CVA, will not come to you for follow up. It may not be totally unbelievable when somebody says that the carotid irradiation may increase CVA's. There is a name to this bias which I donot remember, which actually develops when the patients who come for follow-up without any symptoms reinforces a erroneous perception that the treatment actually was not toxic, whereas actually these patients donot represent the universal set of patients. These things can only be known from a well done retrospective study (without any lost to follow up) after a decade of treatment.
The disease specific survival in my study which included 1000 patients of early glottic cancer was 96%. The major causes of death among these patients were non malignant causes followed by second cancers, both of which were more than deaths related to glottic cancer.
Hi Chili ,
are you talking about the following type of bias ? just looked it up and found this - "selective reporting of results within primary studies ("outcome variable selection bias") (Hutton and Williamson 2000; Hahn et al. 2000; Hahn, Williamson and Hutton 2002) also known as "within-study reporting bias"
very interesting discussion guys -any inputs on tolerance of altered fractionation (even a SIB ) with concomitant chemotherapy in HNC ?
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