Induction vs Concurrent chemotherapy in Head and Neck Cancer

In the green journal today there is an update of the Pignon Meta-analysis for radiation and chemotherapy.

87 trials with 16,485 patients. With chemotherapy in addition to radiotherapy, HR for death was 0.88 (p less than 0.0001) with an absolute reduction of mortality of4.5% at 5 year. There was an interaction (p less than 0.0001) in chemotherapy timing, i.e. adjuvant, induction or concomitant. Concomitant chemotherapy was superior to induction chemotherapy, with HR 0.81 (p less than 0.0001) absolute reduction of 6.5% at 5 years. Chemo was also of less utility with older patients (p = 0.003, test for trend).

Thus more fuel for the induction vs. concurrent debate. One must point out though that the Posner trial however used induction and concurrent chemotherapy, thus a comparison of optimal induction with concurrent treatment vs. optimal concurrent chemoradiotherapy remains unanswered...

Reirradiation for Reccurrent H&N cancer

AC presents today on a case of recurrent nasopharyngeal cancer, treated initially with 65Gy in 1992. Pt experienced Lhermitte's sign (shooting shock like sensations, particularly with neck flexion). - Of note this is not associated with the later development of myelopathy.

in 2007 developed R ear fullness and decreased hearing. CT scan demonstrated mass in the R parapharyngeal space, extending superiorly to the sphenoid sinus and invasion into the clivus. There was also opacifation of the R mastoid air cells. MRI confirmed mass. Biopsies were only positive for radiation change.

in 2008 mass progressed, and at this time the mass was biopsy positive for recurrence NPC.

15-50% of H&N cancers develop local failiures. Incidence of 2nd primary tumors is around 14%, with 1/3 of these in the H&N. (note that with NPC often recurrences are distant, and can be quite delayed).

Options include resection +/- RT, Reirradiaiton +/- CT, or palliative chemo. MS is <10 months, OS at 1 year is less than 35%.

Surgical salvage results in 5y OS of 10-25%. Operative mortality close to 5% (Goodwin, Laryngoscope 110:1, 2000.)

Reirradiation is primarily limited by normal tissue tolerance (carotid artery stenosis/rupture, osteoradionecrosis, non-healing ulceration, myelopathy). Disease free intervals of less than 6months suggests persistent disease, likely resistant to the initial treatment regimen.

Approach includes review of the initial treatment portals: was there a geographic miss? What were the doses to normal tissues.

Non-randomized series of postoperative RT after resection (in highly selected patients) result in 3y OS of approximately 44% (Kasperts Cancer 2006;106:1536. also De Crevoiseier Cancer 2001;91:2071.) Acute Grade 3-4 toxicities are around 50% reported, late effects are near 40%, but likely these are underreported. Actuarial calculations are lacking in this, and are a necessity for a true accounting.

Janot JCO 26:5518, 2008 - GORTEC group. 130 with complete resection after recurrence - randomized to observation vs 60Gy BID, with 5FU + HU (week on, week off style Chicago regimen). - Acute mucositis G3-4 28%. Late G 3-4 toxicity in the RT arm was approximately 40%. HR for LRC for RT was around 2.7 (60% at 2years for RT arm, SS), but no difference in overall survival. DFS was statistically improved and was the primary endpoint. Note that around 1/2 of the observation arm recieved salvage treatment with the same regimen, and this would dilute the OS benefit.

RTOG 9911 Langer JCO 25:4800, 2007. n=99. Recurrent unresectable cancer in prior RT field. Recieved 60Gy 1.5Gy BID with concurrent CDDP + paclitaxel (week on week off). Median f/u 24months. Acute grade 4 at 28%. Grade 4 late toxicity 17%, 8 treatment related deaths, many of these carotid rupture. 2yr OS 26%. Able to achieve a maximum dose to cord of 12Gy.

Sulman IJROBP 73:399, 2009. MDA series using IMRT in 78 patients. 2yr OS 58%, 2 yr LRC 64% (though many of these were recurrent and resectable). Median reirradiation dose was 60Gy.

Also MSKCC series (Lee, IJROBP 68:731, 2007), showed 2 yr OS 37%, with 70% treated with IMRT. Late toxicities at 15%. MVA showed association with improved LRC with IMRT (but this has some leadtime bias built in). Around 1/3 were treated after re-resection.

To return to the case - prescribed 70Gy to the tumor alone, with very tight margins close to 1-2mm, with daily OBI, weekly conebeam. Treated 6 fractions per week (ala DHANCA) with concurrent CDDP. No elective treatment due to the risk of severe morbidity.

Nasopharynx

DPB presents a case of Nasopharynx for Resident Report this morning.

63 yo WF with history of R fullness. Biopsy of R level V positive for poorly differentiated carcinoma. CT of neck reveals bilaterally enlarged nodes. FOL reveals a mass in the R fossa of Rosenmeuller. EUA biopsy revealed poorly differentiated carcinoma and tested postive for EBV DNA. Staged as a T1N2.

Staging

• T1 - confined to nasopharynx
• T2 - extends to soft tissues
  • T2a - extends to oropharynx and/or nasal cavity
    
  • T2b - any tumor with parapharyngeal extension
• T3 - involves bony structures and/or paranasal sinuses
• T4 - intracranial extension and/or involvement of cranial nerves, infratemporal fossa, hypopharynx, orbit, or masticator space
  

• N1 - unilateral nodes, 6 cm or less, above the supraclavicular fossa
• N2 - bilateral nodes, 6 cm or less, above the supraclav fossa
• N3a - lymph node greater than 6 cm
• N3b - extension to the supraclav fossa
  

Special attention should be to the neurologic exam, as 20% have CN palsies.
Endemic to the Chinese population, and associated with EBV infection.
Obstruction of the Eustachion tube can cause a serous otitis media.
70-90% LN involvement, with 50% having bilateral involvement. Important to note that Level V is very frequently involved, and there is occaisional level IB involvement.

Teo IJROBP 1996 demonstrated that parapharyngeal invovlement was associated with worse DM and worse overall survival in the setting were other high risk factors were not present.

WHO classification of NP type 1 keratinizing squamous cell, type 2 non-keratinizing SCC, type 3 undifferentiated carcinoma. Lymphoepithelioma are carcinomas with a background of lymphocytes, and may have better outcomes.

For simulation, fusion of MRI with a planning CT with IV contrast is ideal.

Al-Sarraf Int 0099 stage III or IV, randomized to RT or RT+CT and adjuvant CT.
70Gy used to the primary at 1.8-2Gy day, 60Gy to nodes <2cm, 50Gy to elective nodal regions. CDDP 100mg/m2 x3 used during RT, adjuvant CDDP + FU (only 50% compliance however).
OS 78% vs 47% SS
Closed early due to survival benefit. PFS was also lower in the control arm than expected.

There are multiple other randomized trials from PMH and Asia which confirm benefit of RT. Metaanalysis in 2006 also showed a benefit to CT combined with RT, and suggests that concurrent may be the treatment of choice.

IMRT experience from UCSF from Lee IJROBP 2002, shows promising control rates, with dosimetric sparing of critical normal structures. There is also a randomized trial on this subject from Hong Kong (see link). This demonstrates significant improvement in objective measures of salivary flow, though the quality of life was no different amoung the arms.

Induction Chemotherapy for Head and Neck Cancer

There is a good editorial in the JCO about induction chemotherapy for head and neck cancers, which sums up the arguments against adopting it as a standard of care prematurely.

Link

RT in the AM better than in the PM?

File this one under odd randomized trials:

This Candian Trial randomized 216 patients undergoing RT for head and neck cancer were randomized to recieve RT in the morning (8-10AM) vs RT in the afternoon (4-6PM).  Why, you ask?  This is based on observations that oral mucosal cells exhibit a circadian rhythm tend to be in G1 in the morning and in M by the afternoon.  Thus RT should be less toxic to the mucosa in the AM.  

They didn't quite find statistical significance on their main endpoint, they did find some subgroup signals.  

http://www.redjournal.org/article/PIIS0360301608030356/abstract?rss=yes

Hyperthermia in the Netherlands

Dr. Maarten Paulides from Erasmus in the Netherlands - an engineer associated with their Hyperthermia project - spoke about their current clinical efforts.

Background

12- year update of the netherlands deep ht trail

doi:10.1016/j.ijrobp.2007.07.2348    

114 pts with locally advanced cervical cancer

1990-1996

ebrt + brachytherapy in all patients to 68-70Gy to point A

randomized to ht once weekly with heating goal of 42 degrees C for 60 minutes

local control 37% rt vs 56% rtht (p=0.001)

overall survival 20% rt vs 37% rtht (p=0.03)

actuarial > grade ii late toxicity was no different between arms

This is one of the strongest trials supporting a clinical benefit to hyperthermia with radiation therapy in the curative settting.  The primary weakness is that this trial occurred prior to the NCI alert in 1999 supporting the use of concurrent cisplatin based chemotherapy.

This weakness is addressed in an ongoing multi-institutional trial, currently open at Duke, exploring radiation therapy with concurrent cddp based chemo, plus or minus hyperthermia.

Current HT Clinic load at Erasmus:

deep ht - ~100 patients/year - 1.5 hour treatment time (0.5 hours of this is warm up), treated once weekly.

superficial ht - ~60 patients/year - 1 hour treatment times (0.25 hours for warmup), treated once weekly.

Ongoing ht trials at erasmus:

phase iii cervix trial (noted above)

recurrent rectal cancer: capcetabine + HT in previously irradiated patients

developing head and neck applicator

Head and Neck

Dr. Paulides referenced the below as backgound.

valdagni ijrobp 1994 (PMID: 8270437) 

small randomized trial of RT +/- HT in locally advanced head and neck cancers

in 44 nodes (41 patients) the response rate was 41% rt vs 83% rtht

this trial also reported improve nodal control and overall survival at 5 years, though one must take the number of patients into account.

With this backdrop, the physicists and engineers at Erasmus have been developing a head and neck collar applicator for hyperthermia delivery, which has now been used for treating patients.  Monitoring is a bit of a problem as many of these sites are not accessible or amenable to invasive thermometry.  Addtitionally cooling from vasculature and respiration may confound attempts for homogeneous heating of the target.  However, he was able to show that this could be done, and I for one was quite surprised that they were implementing this in patients already, including a nasopharyngeal patient which he showed the thermometry for.  

Link to an Abstract describing the applicator (the Hypercollar): http://www.esho.info/esho2007/pdf/paulides1_esho2007.pdf