Is Cetuximab really that good?

[Palex80]

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So, what's your feeling about Cetuximab-induced mucositis.

In the Bonner trial the rate of mucositis in the Cetuximab-RT group was not higher than in the RT group. However there are some studies, suggesting even higher rates of Mucositis with Cetuximab-RT than with Cisplatin-RT.
http://www.ncbi.nlm.nih.gov/pubmed/21159400

I am currentling struggling with an older patient receiving Cetuximab-RT and whose mouth looks at 40 Gy worse than many mouths I've seen after 70 Gy RT.
Surely this is a single case and he did develop quite a rash early on, but what bothers him the most right now is an increasing mucositis over the past couple of weeks.

It makes sense to think that EGFR-antagonists would also target cells in the oral mucosa, but why wasn't the mucositis rate higher in the Bonner trial? There are just so many questions unanswered in this trial, including the underpowered analyses which showed that only :

a) CCB-patients
http://www.ncbi.nlm.nih.gov/pubmed/16467544
`
b) patients younger than 65 year old and with good performance index
http://www.ncbi.nlm.nih.gov/pubmed/19897418

profited from Cetuximab.

Your thoughts?

 

[Gfunk6]

I think this may be a case of an unusually severe reaction to XRT rather than a combination of XRT and cetuximab. We don't generally see worse than usual mucositis with the combo.

Personally I favor CDDP over cetuximab, but once the head to head trial is complete I guess we'll know for sure. Ironically, the patient populations for which cetuximab may be recommended over CDDP (old, co-morbidities, lower KPS) probably benefit the least.

 

[deleted171718]

Doesn't directly address the question of CDDP vs C225 but still relevant to this discussion (CRT w/CDDP +/- C225).

RTOG 0522

No hint of a difference in PFS or OS. G3-4 mucositis worse w/Cetuximab (35% v 45%).

 

[TarHeelRadOnc]

Doesn't directly address the question of CDDP vs C225 but still relevant to this discussion (CRT w/CDDP +/- C225).

RTOG 0522

No hint of a difference in PFS or OS. G3-4 mucositis worse w/Cetuximab (35% v 45%).

Admittedly, I am bias as I live in the IgE-mediated C225 hypersensitivity zone and couldn't convince any of my med oncs to give Cetuximab anyway, but the recent data with C225 seem underwhelming. Obviously the negative results of 0522 are a crushing blow. In addition, a reasonably large retrospective study from MSKCC (PMID:20947269) suggests that single agent concurrent CDDP is superior to single agent concurrent C225. C225 still an option for elderly and pts with poor PS/renal insufficiency/etc, but I feel strongly that CDDP should be preferentially used in eligible patients.

 

[Gfunk6]

Obviously the negative results of 0522 are a crushing blow.

I'm not sure I agree here for the reasons CaptainKuru stated. 0522 didn't really compare CDDP vs C225 head-to-head. In fact, from a marketing perspective, it was really a stroke of genius because regardless of the outcome it would not answer the question of CDDP vs C225 superiority.

However, now that RTOG 1016 is finally off the ground, we may yet get the definitive answer to this question.

 

[TarHeelRadOnc]

I'm not sure I agree here for the reasons CaptainKuru stated. 0522 didn't really compare CDDP vs C225 head-to-head. In fact, from a marketing perspective, it was really a stroke of genius because regardless of the outcome it would not answer the question of CDDP vs C225 superiority.

However, now that RTOG 1016 is finally off the ground, we may yet get the definitive answer to this question.

Good point.

What I was trying to say (not so eloquently) was that concurrent CDDP is the standard of care for stage III-IVb HNCA (role of systemic therapy obviously debatable in T1-2N1 dz). CDDP is supported by an individual patient data meta-analysis with >10,000 patients showing a 6.5% 5yr survival benefit. Concurrent C225 is supported by a single randomized trial of 424 patients. Several retrospective reports now emerging suggesting superiority of CDDP to C225. Needless to say, burden of evidence in favor of CDDP. Would be great for C225 if it were beneficial when added to standard CDDP, but that doesn't appear to be the case. Thats why I called it a crushing blow. I have concerns that RTOG 1016 won't accrue...

 

[medgator]

Good point.

What I was trying to say (not so eloquently) was that concurrent CDDP is the standard of care for stage III-IVb HNCA (role of systemic therapy obviously debatable in T1-2N1 dz). CDDP is supported by an individual patient data meta-analysis with >10,000 patients showing a 6.5% 5yr survival benefit. Concurrent C225 is supported by a single randomized trial of 424 patients. ..

A single randomized trial that was drug company sponsored and had a control arm of XRT alone, with altered fractionation being optional in those patients.

 

[kimplera]

Hopefully given the selection of only patients with p16 positive (presumed HPV positive) tumors this trial will accrue. This is a particularly important question given the profound differences in survival between patients with HPV+ tumors and HPV- tumors and the potential role of HPV in altering EGFR expression.

I have concerns that RTOG 1016 won't accrue...

 

[Mandelin Rain]

I have concerns that it won't accrue because there is no standard arm.

Sure, CDDP+XRT is an arm, but it isn't standard therapy. Rather, it is the altered fractionation + 2 cycles cis that was negative in the last RTOG failure 0129. Mind you, that wasn't a trial for equivalence or even non-inferiority, it was for head to head superiority. Somehow, the experimental (and losing) arm becomes the standard arm for the next trial? Does this make sense to anyone?

 

[RadRadRad]

I have concerns that it won't accrue because there is no standard arm.

Sure, CDDP+XRT is an arm, but it isn't standard therapy. Rather, it is the altered fractionation + 2 cycles cis that was negative in the last RTOG failure 0129. Mind you, that wasn't a trial for equivalence or even non-inferiority, it was for head to head superiority. Somehow, the experimental (and losing) arm becomes the standard arm for the next trial? Does this make sense to anyone?

I agree. I think most people would prefer to use SIB or SF. I pasted the rationale given in the trial below. My guess is that since Bonner study showed Cetux only benefited those with altered fractionation RT, they felt ACB was needed in at least this arm and by minimizing differences between the two arms they get a cleaner study thus ACB for CDDP arm as well.

Analysis of RTOG 0129 revealed that patients randomized to receive either accelerated
fractionation radiotherapy with concomitant boost with 2 cycles of high-dose cisplatin or
standard fractionation radiotherapy with 3 cycles of high-dose cisplatin had similar overall
and progression-free survival. The hazard ratios associated with treatment assignment
were similar among HPV-positive and HPV-negative patients. Although there were no
differences in high-grade acute or late toxic events, several toxicities known to be
associated with cisplatin were significantly lower in the 2 versus 3 cycles, including
hematologic and metabolic toxicities. However, late grade 3-4 mucous membrane toxicities
were higher in the accelerated arm (4% vs. 1%, p=0.04). In addition, in RTOG 0129, only
69% of patients treated with SFX received all 3 planned cycles of cisplatin, while 88% of
patients treated with AFX-C received both planned cycles. Thus, the accelerated arm had
higher treatment compliance and fewer cisplatin-related hematologic and metabolic events.
In a non-inferiority design, per-protocol analysis is usually considered as a sensitivity
measure in addition to intent-to-treat analysis, so it is essential to have good compliance.
• Based on these aggregate data suggesting the benefit of acceleration in RT alone and
acceleration in RT + cetuximab, the transmutability of time, and chemotherapy
(acceleration~1 cycle of chemotherapy), and the need to control for time as a treatment
variable impacting tumor repopulation, accelerated fractionation (with 2 cycles of cisplatin in
arm 1) has been selected for both arms of this trial.

 

[Mandelin Rain]

The real question is why run a trial at all if the losing expirimental arm is destined to become the new standard arm for the next?

 

[Gfunk6]

Scientific research is not simply the objective search for truth. It is also replete with political agendas, bias, compromise, and pharma financial interests. Some of the "best" trials failed to accrue. It is better to run a "compromise" trial which has a high probability of meeting accrual goals then a "pure" one that does not.

 

[Gfunk6]

Just saw this article in the Red Journal. Palex, were you a co-author?

Link

Int J Radiat Oncol Biol Phys. 2010 Aug 21. [Epub ahead of print]
Grade 3/4 Dermatitis in Head and Neck Cancer Patients Treated with Concurrent Cetuximab and IMRT.
Studer G, Brown M, Salgueiro EB, Schmückle H, Romancuk N, Winkler G, Lee SJ, Sträuli A, Kissling B, Dummer R, Glanzmann C.
Source
Department of Radiation Oncology, University Hospital Zurich, Zurich, Switzerland.
Abstract
PURPOSE:
To assess the rate of serious (>Grade 2, CTCAE 3.0) dermatitis in our head-and-neck cancer (HNC) patients undergoing simultaneous integrated boost intensity-modulated radiotherapy with concomitant cetuximab (SIB-IMRT-cetuximab). We hypothesized a positive association between the radiation dose to the skin and the degree of dermatitis in patients receiving cetuximab.

METHODS AND MATERIALS:
Between April 2006 and December 2009, 99 HNC patients underwent SIB-IMRT-cetuximab. In 69/99 (70%), systemic treatment consisted of concomitant cetuximab only, whereas 30 (30%) were switched from concomitant cisplatin to concomitant cetuximab. Treatment-related dermatitis was prospectively monitored. Ninety-nine patients treated with four to seven concomitant cycles of cisplatin only served as an internal control group. The radiation dose delivered to the skin was measured and related to dermal reactions.

RESULTS:
Grade 3/4 dermatitis developed in 34% of the cetuximab cohort, which was substantially higher than in the control cohort (3%, p < 0.01). No cases of skin necrosis or other fatal events related to cetuximab have occurred so far. A significantly larger mean skin area was found exposed to high radiation doses in patients with severe cetuximab-related dermatitis, compared with those without (p < 0.01).

CONCLUSION:
Concomitant cetuximab resulted in a approximately 10-fold increase in the rate of severe transient dermatitis compared with the use of concomitant cisplatin. We found a positive association between the incidence of Grade 3/4 dermatitis and the radiation dose delivered to the skin in patients receiving cetuximab.

 

[Palex80]

Just saw this article in the Red Journal. Palex, were you a co-author?

Link

No, I was not a co-author.
This is however a very interesting article.

 

[Gfunk6]

So here's a cetuximab-related issue that recently came up in my practice.

What chemo do you give for your average 70+ year old patient with Stage III/IV H&N with the usual co-morbidities? According to the MACH paper, conventional chemo use should not be routine in this age group. I guess the other alternative is hyper-frac but the acute toxicity can really hurt.

Is cetuximab the only true answer?

 

[deleted4401]

My thought is that you can use Erbi or single agent taxane or carbo/tax or lower dose cis OR you do something similar to hyper-fx by using IMRT to do a SIB/dose paint. You shorten overall treatment time, and the (limited) data indicates good outcome with acceptable toxicity.

Unfortunately, it's not your choice. Med onc will decide.

Funny - started looking at the chemotherapy notes and calculating what doses are... Interesting that many community docs don't give the chemotherapy doses we know and love... Called a few on it, and they made the changes.

S

 

[medgator]

So here's a cetuximab-related issue that recently came up in my practice.

What chemo do you give for your average 70+ year old patient with Stage III/IV H&N with the usual co-morbidities? According to the MACH paper, conventional chemo use should not be routine in this age group. I guess the other alternative is hyper-frac but the acute toxicity can really hurt.

Is cetuximab the only true answer?

I'm sure the med oncs would chime in with carbo, and it was used in the induction TPF studies, but I think the data for it is scant.