qa-with-dr-cohen-on-adjuvant-therapy-for-head-neck-cancer-audio-podcast

qa-with-dr-cohen-on-adjuvant-therapy-for-head-neck-cancer-transcript

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This program was made possible through an educational grant from Eli Lilly, who had no input in its content.  We thank them for their support.

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Here are the links to the audio and video podcasts, the transcript, and the figures for the program

dr-cohen-adjuvant-therapy-for-head-neck-ca-audio-podcast

dr-cohen-adjuvant-therapy-for-head-neck-ca-transcript

dr-cohen-adjuvant-therapy-for-head-neck-ca-figures

We thank Eli Lilly Oncology for their support of this educational program.

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dr-alex-lin-rad-onc-hn-cancer-q-a-audio-podcast

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dr-alex-lin-rad-onc-hn-cancer-q-a-figures

We appreciate the educational grant support from Eli Lilly that made this program possible.

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Combined chemoradiotherapy is a standard therapy for the treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN) (webinar on both curative radiation and curative chemoradiotherapy to come within the next few months).  Response rates are high, and cure rates surpass 50%, even for stage III and IV disease.  Head and neck cancer tends to spread to the lymph nodes in the neck, and the neck is typically covered in the radiation field.  Those patients with cancer remaining in the neck after chemoradiotherapy clearly need these nodes removed surgically to elicit a cure.  But what about those who have a complete response, as judged by CT imaging?  Are outcomes improved by elective lymph node dissection after successful chemoradiotherapy (as judged by CT) or is this just unnecessary surgery?

I think that the majority opinion right now leans towards neck dissection for most patients with N2 or N3 disease at presentation.  Those who feel this way argue that neck dissection can improve local control and point to series showing that neck dissections find residual disease in about a quarter of patients.  Older data showed advantages both in local control and disease-free survival for neck dissection and ASCO guidelines for larynx cancer endorse this perspective.

But have things changed with better chemoradiotherapy?  In more modern series, the disease control advantage is less clear.  Isolated neck recurrence has become rare in patients with complete response to chemoradiotherapy-it’s now under 5%.  A JCO paper in 2006 showed a lack of survival advantage for elective lymph node dissection for patients with complete response on CT.  Investigators at the University of Florida looked back at 550 patients with node positive SCCHN treated with radiation therapy (76%) or chemoradiotherapy (24%); 62% also had elective lymph node dissection.  All patients had CT imaging a month after the completion of therapy.  Of those patients who had neck dissection, the negative predictive value of being NED on CT imaging was 94%.  Of 32 patients with radiographic complete response and no elective lymph node dissection, the five year neck-control rate was 100% and cause-specific survival was not different from patients with neck dissection.  NCCN guidelines follow this perspective, listing active observation as a treatment option.

Why am I blogging about this now?  A new study presented this week (6/4/10) at ASCO studied this question in a very large series from MD Anderson Cancer Center.  They looked back at their experience over a decade from 1994 to 2004.  During this period, the institutional policy was to not perform elective neck dissection for patients with a complete nodal response to irradiation.  They looked back at 935 patients and found that half had a complete nodal response in the neck as judged by CT.  The key finding was that among patients with complete nodal response and no elective neck dissection, there was only a 4% incidence of neck-only recurrence.  This suggests that those patients with complete nodal response on CT from chemoradiotherapy can safely forgo elective neck dissection.  One subgroup was notable-hypopharynx patients with big nodes at presentation had high failure rates, even when they had a complete nodal response, suggesting that this group may benefit from additional therapy, such as elective nodal dissection.  One final finding was of note from this study, and it is consistent with previous literature.  Among patients who did have a nodal dissection, prognosis was better when there was a pathologic complete response (no residual living cancer cells in the nodes taken out).  This makes common sense-if the main therapy kills all your cancer cells, you do better!  What’s harder is to know what to do with those patients with residual cancer on elective node dissection.  Should they be given additional therapy to try to improve their cure rates?  Or, has their cancer demonstrated that it is not sensitive to our therapies, meaning that this extra therapy would only cause toxicity without added cancer control?

Where do we go from here?  How big of a surgery is needed?  Are there other patients who can be spared neck dissections?    Are there clinical, staging, radiographic or biologic variables that can define patients who do benefit from elective lymph node dissection?  Can PET/CT imaging help define additional patients who can safely forgo elective lymph node dissection?  I think that the last of these ideas bears the most promise.

Between 1994 and 2004, when the 2010 ASCO study was done, PET/CT imaging was not a standard part of head and neck care.  CT scanning has key limitations in SCCHN.  Even in cured patients, imaging findings can take a long time to return to normal and sometimes never do, secondary to scar tissue.  So, CT may fail to capture many of the patients who have had a complete response.  I believe that PET/CT has the potential to improve care in head and neck cancer, and several abstracts show its promise in other contexts.  A small study published in 2004 in JCO already showed that the combination of PET/CT and sentinel node biopsy (biopsy of the first draining node from the primary tumor) might substantially reduce the number of unnecessary elective nodal dissections.  Hopefully, future studies will help further define who really needs surgery, and who does not.

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dr-lin-rad-onc-hn-cancer-radiation-intro-audio-podcast

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After we post the podcast of the Q&A session that followed this presentation by Dr. Lin, we’ll post another podcast by Dr. Ezra Cohen, medical oncologist at the University of Chicago, on chemotherapy in the post-operative setting for head/neck cancer.

We thank Eli Lilly Oncology for their educational grant supporting this program.

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Ask any cancer survivor what his or her greatest fear is, and chances are he or she’ll reply: “The cancer coming back.” Recurrence rates from different cancers can vary widely, from 5 to 95 percent depending on how far the original tumor had spread, its particular molecular characteristics and other clinical factors. But what makes cancer come back?

A possible answer may get to the root of the cancer problem: cancer stem cells (CSCs).

CSCs can be thought of as generals in a war. There aren’t very many of them, they are located at the rear, and organize the battles and send in the troops to invade. They build the armies. Many scientists believe that CSCs originate and keep tumors growing, invading and spreading into new places. They also may make up less than 0.1 percent, or one in 1,000 cells, of a solid tumor’s bulk. They are not related to embryonic stem cells, other than their name who indicates that they are at the root of an event; in the case of embryonic stem cells it means that they give rise to an embryo, in the case of CSC it implies that they give rise to cancer.

The reason many scientists support the notion that there is a possible two-tiered system in cancers is that it helps explain many observations that have puzzled clinical investigators for decades. If an epithelial cell renews every 4-12 weeks as do skin or mouth mucosa cells, how can one explain that experiencing sunburn as a child increases the risk of melanoma at ages over 50? Normal epithelial stem cells-which keep tissues like skin and the lining of the colon, lungs and other organs regenerating and therefore alive-divide slowly and live long. They may accumulate genetic damage from carcinogens we’re exposed to in air, water and food, and with enough genetic damage, they give rise to what we call cancer-cells that divide very quickly and out of control. So in essence this would mean that cancer arises not just from any cell, but from those progenitor stem cells that carry over all that acquired genetic damage until it goes out of control giving rise to a tumor.

Traditional cancer treatments-chemotherapy and radiation-target fast-dividing cells. CSCs divide slowly. Chemo and radiation doesn’t kill them, and they live on to make new tumors in close-by and distant places. It might take just one cell for a tumor to relapse. That has been shown in a leukemia experimental system. If you see a complete destruction of a tumor but have one or two surviving cancer stem cells, you could have a recurrence. Normal stem cells check how they are doing. If there are too many gene alterations, they commit suicide. Cancer cells and CSC don’t look at DNA damage. They keep dividing despite mutation after mutation, which in turn is advantageous because it gives them new abilities to evade our current treatments. Until we identify what makes cancer stem cells survive, we won’t be able to cure solid tumors. Cancer is so much more complex than we thought 30 years ago, and the CSC model of cancer helps explain much of that complexity.

We have to understand normal stem cells, normal development of organisms and tissues, and many of the normal pathways of maintaining a state of equilibrium, because we know if those pathways are mutated it can cause cancer. Where normal epithelial adult stem cells divide evenly, making one daughter cell and one stem cell, CSCs may divide unevenly, creating multiple damaged daughters and CSCs, a theory some scientists say explains rapid solid tumor growth. Combine this with the idea that CSCs can change hats midstream and lie dormant for years before rearing up again, and you might begin to fathom why people still die from solid tumors like breast, lung and prostate cancer 39 years after war was declared on cancer by President Nixon.

There have been very solid advances in the CSC field in identifying these cells in breast, brain, and pancreatic cancers, and in leukemia and other hematologic malignancies (Dick et al). For HNC the data is less widespread, with a group that identified a marker CD44 that seems related to CSC (Prince et al). Our research group at the University of Colorado has linked CSC to resistance to conventional therapy in HNC, and a means to inhibit that using drugs (Keysar et al). For this we utilize a direct patient tumor model (DPTM) where tumors are derived directly from patient’s surgeries for HNC instead of using commercial cell lines. Our preliminary data suggest that, at least in head and neck cancer, new tumor development falls to cancer stem cell theory.

It’s possible that not all CSC are the same. Some could be closer to a normal adult stem cell and may be more susceptible to traditional therapy, which would explain why some cancers do not recur. Perhaps if the cancer stem cell has many gene mutations, it makes the tumor less susceptible.

In summary, it seems CSC are the cells of origin of many cancers probably including HNC. Therapies are being proposed and developed that specifically inhibit mechanisms utilized selectively by CSC. In the future, doctors would likely debulk the tumor first using surgery, traditional chemotherapy and radiation, then use antibodies or drugs to go after any residual cancer stem cells, which we think are responsible for tumors recurring.

Cancer is so much more complex than we thought 30 years ago. It has been a tough opponent because it is tremendously complex and it has a phenomenal ability to adapt. It can shut down and weather the storm. The next frontier in cancer research is to answer questions related to CSC: Are cancer stem cells generating cancer, driving it or sustaining it? It’s likely that not all cancer stem cells are the same.

Additional reading on the subject:

Dick JE. Looking ahead in cancer stem cell research. Nat Biotechnol. 2009 Jan;27(1):44-6.

Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, Weissman IL, Clarke MF, Ailles LE. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci USA. 2007 Jan 16;104(3):973-8. Epub 2007 Jan 8.

S. Keysar, R. Anderson, S. Takimoto, A. Tan, I. Deyneko, K. McGovern, R. W. Ross, J. Song, A. Jimeno. Combined hedgehog and epidermal growth factor receptor (EGFR) inhibition in a direct patient tumor model (DPTM) of head and neck squamous cell cancer (HNSCC). 2010 ASCO Annual Meeting, J Clin Oncol 28:7s, 2010 (suppl; abstr 5558)

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Phase II study of figitumumab in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck: GORTEC 2008-02

Figitumumab is an antibody that inhibits the insulin-like growth factor receptor.  As a single agent, it does not appear to be active in platinum-refractory SCCHN.

BIBW 2992 versus cetuximab in patients with metastatic or recurrent head and neck cancer (SCCHN) after failure of platinum-containing therapy with a cross-over period for progressing patients: Preliminary results of a randomized, open-label phase II study.

BIBW2992 is a pill that inhibits both EGFR and HER2.  I believe in the potential of inhibiting both EGFR and HER2 enough to have opened a trial of it with a related drug.  Response rate here was 18%, at least as good as the 8% seen with cetuximab, reinforcing the idea that this general strategy is worthy of further testing.

Long-term results in a cohort of medullary thyroid cancer (MTC) patients (pts) in a phase I study of XL184 (BMS 907351), an oral inhibitor of MET, VEGFR2, and RET.

The maximum tolerated dose in this large phase I study was 175mg daily.  There was strong evidence of activity-29% partial response, 4 additional patients with at least 30% shrinkage at some point, and 41% stable disease for at least six months.  There were responses in patients with and without RET mutations.  A phase III study is ongoing, which seems warranted based on these results.

Long-term results from TAX324: A phase III trial of sequential therapy comparing TPF to PF in locally advanced (LA) squamous cell cancer of the head and neck (HNC).

Chemotherapy got its start in head and neck cancer given before radiation (called neoadjuvant or “induction” chemotherapy).  We later learned that it was better to give the chemo and radiation at the same time, so concurrent chemoradiation gained favor.  A number of trials now look at adding induction chemotherapy before concurrent chemoradiation (so chemo then chemo + radiation together).  This trial updates published results comparing two different modalities of induction chemotherapy-cisplatin plus 5-FU vs. cisplatin + 5-FU plus docetaxel.  The three drug regimen continues to win with more followup, showing the merits of docetaxel in this therapy.  We will newly see data showing that the effect size was bigger in patients > 55 years of age than in younger patients.  This could be practice changing for those oncologists who use TPF for young patients, but consider it too toxic for older patients.  However, the use of induction chemotherapy itself remains unproven and controversial.  A trial by this same group aimed to answer the “induction vs. no induction” question.  In the general poster session, we will learn that this study closed early, with only 145 patients accrued; based on the abstract, it look like we may see only toxicity, and not efficacy data this year at ASCO.  Here at GRACE, we plan to discuss this topic further on an upcoming webinar.

Phase II induction cetuximab (C225), paclitaxel (P), and carboplatin (C) followed by chemoradiation with C225, P, C, and RT 68-72Gy for stage III/IV head and neck squamous cancer: Primary site organ preservation and disease control at 2 years (ECOG, E2303).

The induction theme continues.  TAX324 is clearly an important study: it re-raises the induction question in an era of chemoradiotherapy and shows the merits of docetaxel in induction chemotherapy.  However, some oncologists, including myself, have criticized the TPF regimen for being too toxic and not feasible.  Too many patients have toxicities that stop them from undergoing full definitive-chemorads, the part of the treatment paradigm that is best proven at this point.  Many of those who criticize TPF feel that the problem is that 5-FU and cisplatin are too toxic, leading to multiple studies of variants on the regimen.  We’ve seen E2303 before at ASCO, where preliminary results looked good, but no survival numbers were presented.  Here they are with more followup.

TPF induction-radioimmunochemotherapy for the treatment of advanced head and neck cancer.

 This study looked at a lot at once: TPF induction, cisplatin plus cetuximab chemoradiotherapy, neulasta, and PET/CTs.  Patients got 3 cycles of TPF, with peg-filgrastim (neulasta) support followed by cisplatin/cetuximab chemoradiation.  Neulasta is a medicine that raises white blood cell counts.  While its use in head and neck cancer, or any curative-intent therapy, is a bit controversial, it addressed the major problem in TAX324-neutropenia (low levels of a particularly important kind of white blood cell).  8 of 152 patients had to stop therapy after induction chemotherapy-I look forward to learning more about these 8 patients at ASCO.  Response rates were good, cisplatin/cetuximab seems promising and the authors feel that PET/CT helped, but I remain most excited to learn about how neulasta affected the feasibility of induction with TPF and to see detailed toxicity and feasibility data.

Induction docetaxel, cisplatin, and cetuximab (TPE) followed by concurrent radiotherapy, cisplatin, and cetuximab and maintenance cetuximab in patients with locoregionally advanced head and neck cancer (HNC): Mature results with HPV analysis.

We’ve seen this study before at ASCO.  If 5-FU is the most toxic part of TPF, perhaps substituting the much less toxic cetuximab for it can decrease toxicity, increase feasibility, and improve treatment results.  Preliminary results of this phase II study continue to look good.  Most interesting, however, is the HPV data.  Dr. Jimeno recently addressed HPV on GRACE, describing the growing data-set showing how much better HPV+ patients do.  This study flies in the face of this, showing excellent and similar results for HPV+ and HPV- patients.  Is it possible that induction chemotherapy can overcome the negative prognostic effect of HPV negativity?

Radiation alone (RT) versus RT with concomitant chemotherapy (CT) in stages III and IV oropharynx carcinoma: Ten-year results of the 94-01 GORTEC randomized study.

This study is a classic in head and neck cancer.  It demonstrated the merits of adding chemotherapy to radiation.  This poster updates the results at ten years, showing that they stand up with a doubling of cure rates at 10 years.

Need for postradiotherapy neck dissection by tumor site and nodal stage for head and neck cancer.

After chemoradiotherapy, should patients still have neck dissection (surgical removal of lymph nodes in the neck)?  This has been a major debate in SCCHN for a long time that rages on.  In this retrospective review, isolated neck failures were similar in number between those who had the surgery and those who didn’t, raising the question of whether the surgery helps or not.  Of course, there’s probably a bias here in that this was not a randomized study-patients who got extra treatment probably got it for a good reason.  Patients with hypopharyngeal N2 disease with nodes over 3cm had particularly high relapse rates, even when the nodes seemed negative after chemoradiation.  The phrasing of the abstract leaves me uncertain that I completely understand the results of this study, so I’m looking forward to seeing the actual poster.  Also, I don’t have strong feelings about who should have nodal dissection because I don’t think that the existing data properly answer the question.  For this reason, I’m looking forward to hearing the discussant’s views.  Finally, consistent with previous reports and common sense, the review shows worse results for those who have residual living cancer cells in the neck dissection after chemorads.  I look forward to discussing with my colleagues what should be done with these patients.  Do they need more therapy to elicit cure?  Or have their cancers proven that they are not sensitive to such therapy, so that it would only cause side effects?

Clinical efficacy and tolerability of continuous course reirradiation with concurrent weekly carboplatin-paclitaxel for locally recurrent, nonmetastatic squamous cell carcinoma of the head and neck (SCCHN).

When SCCHN recurs, it tends to do so locally, rendering recurrence potentially curable by salvage surgery or repeat radiation.  This study looks at a new way to do this.  In particular, most of the existing data is with hydrea/5-FU chemoradiation, but this study uses the more popular carboplatin/paclitaxel.  I hope that the poster shows what kind of therapy the patients got the first time around.

PTEN as prognostic and predictive marker in postoperative radiotherapy for squamous cell cancer of the head and neck.

Radiation is typically given five days per week, with the weekends off.  My radiation oncology colleagues have explained to me that radiation simply does not work on the weekends J  This study compared five day per week radiation to seven day per week radiation, given after surgery.  Patients with high intensity of PTEN staining (a tumor suppressor) gained from 7 day per week radiation, while patients with low PTEN did not.  The study suggests that PTEN may serve as a prognostic or predictive marker in postoperative radiotherapy, and that my radiation friends may eventually have to work a few more weekend days.  Of note, none of these patients got chemotherapy with their radiation, and there is reason to believe that altered fractionation of radiation may be less effective when combined with chemotherapy (so if any of my radiation friends are reading this, please note that it may be medical oncologists who rescue your weekends!)  (And for those who object to my nerdy, pathetic attempts at humor here, I ask you this: If you can’t joke about immunohistochemical markers predicting the efficacy of altered fractionation regimens in head and neck cancer, what can you joke about?)

Use of XPF expression in tumors and XPF single nucleotide polymorphisms to predict clinical outcome in head and neck cancer.

We’ve talked before on GRACE about the potential value of ERCC1 as a tumor marker in lung cancer.  This poster looks at treatment responses divided by levels of XPF expression (XPF is a subunit of the ERCC1 endonuclease that protects DNA against damage from radiation and platinum compounds).  Lower expressers seemed to have better outcomes, including in the oropharynx subset.

Gene expression profiling of oral preneoplastic lesions (OPL) from a prospective prevention trial.

A 21 gene signature may help predict which patients with pre-cancers in their mouth will go on to develop frank cancer.

Comparison of primary site biopsies and transverse surgical sections of squamous cell carcinoma of the head and neck for translational research analysis.

When you do a biopsy, you get only a tiny piece of a tumor.  Even if all of your tests on that biopsy are perfect, you could only be certain about that exact spot.  So, how representative are superficial and core biopsies in SCCHN?  For EGFR, neither type of biopsy correlated well with full surgical specimens.  For Ki67 (a marker for proliferation), core biopsy did not correlate well, but superficial biopsy did.  The implications of this study for translational research are huge-at least for EGFR, we cannot reliably depend on a biopsy as representing the whole tumor.

Association of circulating tumor cells are associated with lymph node metastasis in squamous cell carcinoma of the head and neck region (SCCHN).

 We’ve talked about circulating tumor cells on GRACE before both in general, and in the context of lung cancer.  This study looked at 40 patients with locally advanced SCCHN.  They were able to detect circulating tumor cells in 40%.  There were fewer CTCs in patients with no lymph nodes involved with cancer or only 1 affected lymph node.  In my opinion, CTCs could eventually play a big role in improving care for SCCHN.

Usefulness of interim FDG-PET after induction chemotherapy in patients with locally advanced squamous cell carcinoma of the head and neck receiving induction chemotherapy and definitive chemoradiotherapy. 

Uptake on PET and changes in uptake on PET may be helpful in predicting who will have a complete response to treatment.  Future studies will be necessary to tell use how we can use this information in treatment decisions.

Oropharynx cancer (OPC) in TAX 324: Human papillomavirus (HPV) and survival.

Updated results from TAX324 will be presented in the oral session.  Here, results are divided by HPV status.  The results for the HPV+ group are fantastic at 5 years-78% disease free survival!  What contributes to this result?  Is it just that the HPV + patients are younger and better able to tolerate the aggressive TPF regimen?  Or, is the biology of HPV+ cancer also different, leading to better treatment responses?  Can we reduce the intensity of post-induction therapy for the HPV+ patients to improve their long term functional outcomes?  Even as I dislike the Cis/5-FU backbone of TPF, it’s hard not to admire how much Dr. Posner, Dr. Haddad and colleagues are driving the field!

A population-based evaluation of incidence trends in oropharynx cancer (OP) focusing on socioeconomic status (SES), sex, and race/ethnicity.

In CA, non-Hispanic white males have an increasing incidence of oropharynx cancers, independent of socioeconomic status.

Human papillomavirus (HPV) transmission from oropharyngeal cancer patients to sexual partners.

The good news about HPV is that prognosis with current modalities of therapy seems better.  The bad news is that HPV is transmissible and this study supports the idea that strains that cause cancer really are being transmitted.  Could the HPV vaccine eventually help with this problem?

Relationship between epidermal growth factor receptor (EGFR) gene copy number, p16 status, and outcome in locally advanced squamous cell carcinoma of the head and neck (LASCCHN).

EGFR FISH positive has been reported to be a predictor of bad outcomes in SCCHN.  HPV (measured by p16) has been reported to be a predictor of good outcomes.  It seems that an individual patient is unlikely to have both of these markers at the same time.

Plasma human papillomavirus (HPV) DNA as a potential tool for tumor detection and monitoring response in HPV-related oropharyngeal carcinoma (OP).

This is a basic science study that suggests that we may be able to use HPV DNA in blood to follow therapy.  It’s a great idea and I look forward to human data.

An open-label, randomized, study of h-R3mAb (nimotuzumab) in patients with advanced (stage III or IVa) squamous cell carcinoma of head and neck (SCCHN): Four-year survival results from a phase IIb study.

Nimotuzumab plus radiation was better than radiation alone.  This antibody has the same target as cetuximab.  Because it is fully humanized, it is unlikely to have the same infusion-reaction problem that some parts of the country have with cetuximab.

Phase II trial of the irreversible oral pan-HER inhibitor PF-00299804 (PF) as first-line treatment in recurrent and/or metastatic (RM) squamous cell carcinoma of the head and neck (SCCHN). 

EGFR is only one of several members of the HER family.  Treatments targeting other members have promise in SCCHN.  I’m working on one such trial.  This trial gave a pan-HER inhibitor and demonstrated antitumor activity without any cytotoxic IV chemotherapy.

A phase II study of sorafenib in combination with carboplatin and paclitaxel in patients with metastatic or recurrent squamous cell cancer of the head and neck (SCCHN).

This was an early presentation of only 22 patients in a study with planned accrual of 43 patients.  Early results are very good, but I think that it’s too early to say much.  I’m looking forward to the discussion to better understand why this was accepted to poster discussion at this early stage.

Pemetrexed (P) and bevacizumab (B) in patients (pts) with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): Final results and correlation with TS, MTHFR, and VEGF gene polymorphisms.

Response rate was 30% and median overall survival was 11.5 months.  Although pemetrexed did not show early promise in treating SCCHN, I am interested in these results.  The incurable patient is more heavily pretreated than ever before; because neither of these agents are part of standard curative-intention therapy, they may be new options for these patients.

Is there a role for adjuvant cetuximab after radiotherapy (RT) plus cetuximab in patients (pts) with locally advanced squamous cell carcinoma of the oropharynx? A phase II randomized trial.

Half these patients with oropharyngeal cancer got an extra 12 weeks of cetuximab after cetuximab chemoradiation.  At two years of followup, cetuximab may have resulted in a small improvement both in event free survival and overall survival.  I look forward to seeing the shape of the curves (did cetuximab simply delay recurrence, or truly result in increased cure?)  Also, remember that this is a phase II study; although it was randomized, it’s not a phase III study.  It raises an interesting hypothesis, but does not prove it.

Chemoprevention with erlotinib and celecoxib in advanced premalignant lesions of the head and neck: Results of a phase I study. 

The only thing better than curing cancer is preventing it.  This phase I study looked at erlotinib and celecoxib in patients with pre-cancers.  The goal of a phase I study is to find the right dose-here it was erlotinib 75mg daily plus celecoxib 400mg twice per day.  Response rates in patients with moderate dysplasia (precancer) or severe dysplasia were good, a total of 71%.  A phase II study is planned.

Phase II study and tissue correlative studies of AZD6244 (ARRY-142886) in iodine-131 refractory papillary thyroid carcinoma (IRPTC) and papillary thyroid carcinoma (PTC) with follicular elements.

AZD6244 is a pill that works by targeting MAPK and MEK-1/2.  In this study of 39 patients, therapy was well tolerated.  While there was only one response, many patients had stable disease and progression free survival was over a year.

No related posts.

#5503-Vandetanib (VAN) in locally advanced or metastatic medullarythyroid cancer (MTC): A randomized, double-blind phase III trial (ZETA).

-Medullary thyroid cancer, once incurable, is hard to treat.  Results with chemotherapy (doxorubicin) have been unimpressive, with <40% response rate, short duration of response, and toxicity.  The phase II results with vandetanib, a pill tyrosine kinase inhibitor to VEGF, RET, and EGFR were promising and so I await anxiously the results of this 331 patient trial.

#5504-Phase II trial of sunitinib in medullary thyroid cancer (MTC).

-Sunitinib (sutent) is also a pill TKI.  It’s targets are PDFRa, PDGFRb, VEGFR1, VEGFR2, VEGFR3, FLT3, CSF-1R and RET.  It is already approved for renal cell cancer.

#5505-Phase II study of oral lapatinib, a dual-tyrosine kinase inhibitor,combined with chemoradiotherapy (CRT) in patients (pts) with locally advanced, unresected squamous cell carcinoma of the head and neck (SCCHN).

-Lapatinib is an oral tyrosinke kinase inhibitor of both EGFR and HER2.  EGFR is known to be important in head and neck cancer and HER2 is its preferred dimerization partner.  I am very excited about this trial because I am running a trial of lapatinib plus capecitabine for incurable head and neck cancer.

#LBA5506-An open-label, randomized, phase III trial of zalutumumab, ahuman monoclonal EGF receptor (EGFr) antibody, versus best supportivecare, in patients with non-curable squamous cell carcinoma (SCCHN) of the head and neck who have failed standard platinum-based chemotherapy

-We have seen the efficacy of cetuximab in head and neck cancer, but in some areas of the country infusion reactions are a big problem.  This trial is of a monoclonal antibody with the same target as cetuximab, but fully humanized, so that it shouldn’t have this problem.

#5507-A phase III trial (RTOG 0129) of two radiation-cisplatin regimensfor head and neck carcinomas (HNC): Impact of radiation and cisplatin intensity on outcome.

-Combined chemotherapy and radiation represents a standard of care for most advanced but curable squamous cell carcinoma of the head and neck.  Before adding chemotherapy to radiation became a standard of care, breaking up radiation in different ways (altered fractionation) was shown to improve outcomes.  With the advent of adding chemotherapy, the benefit has been less clear.  This trial compares one group that gets three cycles of high dose cisplatin plus standard radiation therapy (over seven weeks) to an experimental group only getting two cycles of cisplatin, but accelerated fractionation with concomitant boost (over six weeks).

#5508-Postoperative accelerated radiotherapy (POPART) versusconventional postoperative radiotherapy (CPORT) in squamous cell head and neck cancer: A multicenter prospective randomized study of the Dutch Head and Neck Cooperative Study Group

-Dr. Lin and Dr. Cohen recently conducted webinars on the use of adjuvant radiation that will be available on GRACE within the next few weeks.  One key point was that patients at high risk of recurrence after surgery should have adjuvant radiation and two classes of patients who need radiation should have chemotherapy added to it-those with close margins and those with extracapsular extension in lymph nodes.  This trial randomized patients with either close/positive margins or extracapsular extension to post-operative radiotherapy (66 Gy in 5 weeks) as compared to conventionally fractionated radiotherapy (66 Gy in 7 weeks).  My major question is why no chemotherapy was given, since we know that chemotherapy has a significant benefit for this class of patients.

#5509-Prognostic significance of interleukin-8 (IL-8) and hepatocyte growth factor (HGF) in patients with head and neck squamous cell carcinoma (HNSCC) treated with chemoradiation on a phase III trial

-I am interested to hear about this trial.  We really have only one potential prognostic or predictive marker in SCCHN-HPV.  Can IL-8 and HGH also help stratify patients?

#5510-Analysis of the effect of p16 and tobacco pack-years (p-y) onoverall (OS) and progression-free survival (PFS) for patients with oropharynxcancer (OPC) in Radiation Therapy Oncology Group (RTOG) protocol 9003.

-RTOG 9003 compared several radiation regimens–Twice-Daily Hyperfractionation vs Split-Course Accelerated Hyperfractionation vs Accelerated Fractionation with Concomitant Boost vs Standard Fractionation.  Multiple recent lines of evidence suggest that HPV (as measured by p16) is prognostic in patients treated with chemotherapy and radiation.  We’re learning more recently that the story may be more complicated.  Patients who are HPV+ may not be all the same-those who have the risk factor of smoking in addition to HPV may have a prognosis intermediate between the “pure” HPV-driven cancers and the “pure” smoking driven cancers.  I just heard Maura Gillison talk last week at Penn and she was great; I’m looking forward to learning more about HPV at this talk.

#5519-PTEN as prognostic and predictive marker in postoperativeradiotherapy for squamous cell cancer of the head and neck.

-PTEN is a very famous tumor suppressor gene.  I’m looking forward to learning more about its role as a prognostic and predictive marker in head and neck cancer.

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It has been shown that HPV strains (particularly HPV16) are able to transform and immortalize epithelial cells (make them cancerous) in laboratory experiments. These effects are caused by the E6 and E7 viral capside proteins, which truly function as if they were oncogenes (genes promoting cancer). Once the virus enters the cells and starts multiplying, the E6 and E7 capside proteins (essentially are the bricks that make the outer membrane or cover of the virus) inactivate two key genes, P53 and RB that in normal circumstances are tumor suppressor genes. The interpretation we have for this is that the HPV virus induces permanent multiplication of infected cells (to perpetuate itself) by “taking the brakes off” infected cells, that is, by inactivating proteins such as P53 or RB whose normal function is to control and limit growth. This inactivation leads to protein P16 over-expression, and this is important because detection of P16 has been utilized as a surrogate for HPV infection, in part because it is a simpler marker to detect in a clinical setting. Another aspect further supporting that HPV is an early, causative event of HNC is that genetic analysis typically find HPV genetic material integrated in basically all cells comprising a tumor, which indicates it was present in the original cell that gave rise to it. Whereas there is hope that vaccination of young girls to prevent cervical cancer will decrease HNC as a secondary event, this has yet to be proven. It is unknown at this point whether there is any influence of the immune system on already established cancers.

Accumulating evidence suggests that HPV status is an important prognostic factor, and that patients with HPV positive head and neck cancers have a favorable outcome, compared with those HNC initiated by alcohol or tobacco that are HPV negative. In a recent prospective multi-centre clinical study patients with HPV positive tumors had better responses after neoadjuvant chemotherapy (82% vs. 55%), and after chemotherapy plus radiation therapy (84% vs. 57%) compared to patients with HPV negative tumors.  Subjects with HPV positive cancers had a 33% better overall survival of 33%, and lower risk of progression compared to patients with HPV negative tumors.

The explanation for this better outcome may in part be that unlike tobacco and alcohol-related HNC (where mutations in p53 and RB are present and these pathways are inactivated permanently), in HPV-related HNC these control/override mechanisms are only functionally suppressed.  When chemotherapy and radiation therapy hit the cancer cells and induce DNA damage, these pathways are able to become re-activated, and “put the brakes” on the cancer cell again, leading to its arrest or programmed death (apoptosis). Another reason why patients with HPV-related HNC have a better outcome is that they are usually younger and therefore can tolerate therapy better overall, be it surgical therapy with improved healing, chemotherapy with improved blood count recovery, or radiation therapy where healthier patients are at a significantly lower risk of developing severe complications such as dehydration.  This leads to less interruptions in therapy and a higher percentage of patients receiving all planned treatments, and possibly contributes to a better overall outcome.  A third factor is that the prevalence of heavy smoking or alcohol use history is also lower, and thus these patients have less associated co-morbidities, such as liver, cardiac or lung disease, that have historically limited the intensity of therapy.

On the other hand, because patients with HPV-related cancer are younger and healthier, they have a longer life expectancy, and this has several implications.  The first is that long-term risk of relapse is still a significant concern.  This is because even if the risk of relapsing is (and this is a simplified version for clarity) reduced by a third or half, considering patients live 3 to 5 times longer, the overall number of relapses could be the same or higher.  We currently do not have sufficient information as to the long-term (10 or 20-year) natural history of this relatively new class of HNC.  The second aspect is that the long-term side effects of therapy will likely become more relevant as a deciding factor in planning the therapy.  Advances in supportive medication for chemotherapy and (more importantly) improvements in sparing normal tissues when delivering radiation therapy will very possibly ameliorate those long-term side effects.  We are pending the results of 1) long-term follow-up studies and 2) clinical trials addressing whether therapy should be significantly different depending on HPV status.

Overall these data fully support considering HPV-related HNC as a completely distinct epidemiological, biological and clinical entity, with features that are specific and rather different from HPV-unrelated HNC. Much more research and data will be necessary to fully understand how much therapy is appropriate for each individual patient, modulating the intensity to find the right balance to achieve maximal cure with minimal side effects and impact on quality of life.

Finally, the better prognosis and treatment responses to chemotherapy and radiotherapy by HPV+ tumors may mean that HPV status detection is required to better plan and individualize patient treatment regimes.  This is especially important for HNC from the oral cavity and oropharyngeal regions, where HPV testing will very likely be soon considered part of any routine assessment.

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The first question to ask when addressing incurable SCCHN is to be sure that the cancer really is incurable.  When SCCHN recurs, it often recurs locally, at or near the site of the original cancer.  For this reason, local salvage therapies such as surgery, radiation, chemoradiation or even repeat chemoradiation can sometimes elicit a cure for the patient with a local or local-regional recurrence.  These topics are important and will likely be the subject of future posts on GRACE. The rest of this post will assume that the patient truly is incurable, either because local maneuvers are no longer possible, the cancer has spread to distant sites, or the patient has made a choice to not receive further surgeries or radiation.

Why Chemotherapy for Incurable Disease?

Every cancer therapy has two purposes: to improve duration of life, and to improve quality of life.  Every other measure of chemotherapy success, such as response rate or progression-free-survival, is a surrogate to these two true goals.

For the patient with metastatic disease, chemotherapy is the most important treatment for achieving these two goals.  “Incurable” is not the same as “untreatable.”  Cure means eliminating every last cancer cell.  Treatment means providing real benefit, in the form of achieving these two goals.

Cancer cells are microscopic.  The tip of a pen is the size of more than ten billion cells.  So, if a single cell has spread to a site, say, the lung, you won’t be able to see that cell on a CT or even the most sophisticated PET/CT.  So, once you see the cancer having spread to distant sites, it becomes systemic in more sites than you can see; we call this “metastatic.”  To achieve our two key goals, you need to knock down the cancer everywhere-the places that you can see and those you can’t.  Chemo gets almost everywhere in the body and is therefore the best and most important way to do this for most patients with metastatic disease.

Chemotherapy’s effect on the quality of life question really is a balance.  Chemotherapy can cause side effects, including nausea and fatigue.  However, on the flip side, in addition to prolonging duration of life, chemotherapy also provides a quality of life benefit when successful.  That’s because cancer causes symptoms that chemotherapy can delay or prevent.  For example, many patients with SCCHN have pain and problems swallowing.  When chemotherapy shrinks their cancer, such patients get pain relief and many start swallowing effectively again.  When cancer spreads to bone, it can cause pain and fractures.  When it presses on airways, it can cause shortness of breath and pneumonia.  Cancer causes fatigue, organ failure, blood clots, and numerous other problems.  When chemotherapy relieves or prevents more symptoms than it causes there is a net gain of quality of life.

For a description of the history of chemotherapy, I refer the curious to Chemotherapy Selection for 1st line Non-Small-Cell Lung Cancer (NSCLC) — The Importance of Getting it Right the First Time. This introduction to lung cancer contains a section called “What is cytotoxic Chemotherapy? A brief history of swords to plowshares” that is also applicable to SCCHN. You’ll also note that I self-plagiarized, with adaptation, much of the intro to this chapter—no need to reinvent the wheel!

Believe it or not, there were no positive phase III trials for incurable SCCHN until 2008!

Older studies demonstrated activity of both cisplatin and 5-FU, so in 1992 cisplatin was compared to 5-FU and to the two drugs combined; survival was similar.  Historically, methotrexate was a standard 1^st line regimen for many years, so Arelene Forastiere and colleagues compared cisplatin plus 5-FU and carboplatin plus 5-FU to this older standard.  Toxicity was worse with the new regimens, but there was no statistically significant difference in survival.  Our first hint at genuine improvement came in 2005 when Barbara Burtness and colleagues added cetuximab to cisplatin.  The addition of this targeted agent (cetuximab is a monoclonal antibody against the epidermal growth factor receptor, not a traditional “chemotherapy” drug) showed a strong trend towards improved survival, although it did not reach statistical significance.

The first ever positive phase III trial came in 2008, in the EXTREME trial.  This trial randomized patients to receive platinum + 5FU or this same combination plus cetuximab.  The resulting 2.7 month improvement in survival was both clinically meaningful and statistically significant.  Survival and progression-free survival curves are shown below.

(click on image to enlarge)

To me, the real key point of EXTREME ended up being the principal that cetuximab adds to chemotherapy, not that EXTREME is the be-all, end-all regimen.  To me, there are three key problems with the regimen:

1. Survival is inadequate- While I’d much rather have my patients survive an average of 10.1 months than 7.4 months, 10.1 months is not nearly good enough.
2. The regimen is inconvenient for patients.  The total infusion time in the office for this regimen is almost five hours, and then patients must wear a pump to infuse the 5-FU for four days.
3. The toxicity is way too high.  In fact, I’d call it “extreme”… (groan)

Let’s look at the last problem in a bit more detail.

The EXTREME regimen had an 82% rate of grade 3 or 4 toxicity.  Grade 3 toxicity means “severe adverse event” and grade 4 toxicity means “life threatening or disabling adverse event.”  This ultra-high rate of toxicity is unacceptable for a regimen that does not result in cure.  While it may increase duration of life, other regimens may better promote quality of life.

No Accepted Standard

The EXTREME regimen represents the “textbook” regimen for the functional patient with incurable SCCHN.  However, for the three reasons described above, I have rejected it as a treatment option for my patients.  That does not leave me without effective options to increase duration and quality of life.  It does leave me without level I evidence to support what I do.  As a scientist, I am unhappy and uncomfortable with this situation.  That’s why I have dedicated my life to clinical trials to improve care and provide this data.  I highly recommend that you strongly consider enrolling on a well designed, promising study.  Only with studies will we improve care, and if the experimental treatment really is better, the patients enrolled on the study are the first to benefit.

I cannot say definitively that what I do in practice is the “right” answer; only time and trial results will tell.  In practice, I personalize therapy to the patient’s individual situation based on the data that we do have.  While the goals of chemotherapy are the same for everyone (to improve duration of life and to improve quality of life) patients come with different personal priorities, different levels of functional status, and different levels of other medical problems.  Here is one way to think about regimen choice that I consider reasonable.  I have described it not to provide a “cookbook” or substitute for a trained oncologist’s judgment, but rather to give you some insight into one way to think about these regimens.

Highly symptomatic patient

Some incurable head and neck patients present with dramatic symptoms such as pain and complete inability to swallow.  For these patients, quickly shrinking the cancer becomes the primary goal of therapy in order to relieve symptoms.  In this case, I will often use induction regimens not originally designed for the incurable patient.  My personal favorite of these is the Kies / Wanebo regimen of weekly carboplatin, paclitaxel, and cetuximab.  We will discuss induction chemotherapy in general and this regimen in particular in the future on GRACE (link to follow, once available).

Less symptomatic patient

The average patient has some symptoms, but cares more about longer-term duration and quality of life than speed of tumor regression.  If I had cancer, I’d rather take a regimen that only shrunk my cancer 10%, but stopped it from growing for a year than take a regimen that shrunk it 30% but stopped its growth for only six months.  I’d also want a balance in aggressiveness between working well and not causing too many side effects.  There are two trials and one off-study regimen that I frequently talk to my patients about in this situation (although there are many good trials out there and local availability varies):

ECOG1305- This trial is available through much of the US.  All patients receive their choice of cisplatin plus docetaxel or cisplatin plus 5-FU.  I consider cisplatin plus docetaxel as a reasonable 1^st line regimen for SCCHN and there are multiple phase II trials to support it, although I prefer to use carboplatin for incurable patients due to its superior side effect profile.  I have never chosen cisplatin plus 5-FU when putting a patient on this trial.  The toxicity numbers from the cisplatin/5FU arm of EXTREME, shown above, (76% rate of grade III/IV toxicity) are typical and unacceptably high.  Half of the patients are randomized to also receive Avastin (bevacizumab), a targeted agent that cuts off the blood supply to tumors.  It has proven efficacy in lung cancer, breast cancer, and colon cancer and the trial is asking whether it can also help in head and neck cancer.

UPCC15309- I designed this trial, based on some basic science that I’m not going to get into and two more common sense concerns.  This is a phase II trial in which all patients receive the combination of capecitabine (xeloda) and lapatinib (tykerb) for twelve weeks, followed by maintenance lapatinib.  I wanted a less toxic regimen for my patients, both because side-effects suck (sorry for the crude language, but I think it’s merited!) and out of the belief that with less toxicity, patients could actually get more of the chemo in without delays (hopefully resulting also in better survival-chemo can only work when you take it!)  Right now the trial is only open at UPenn (and our affiliated hospitals Presby and Pennsy), but by the fall of 2010, we hope to also open it at UNC.

Carbo/taxol/cetuximab- For patients without access to trials, I often recommend “Belani regimen” carbo/taxol with weekly cetuximab grafted on.  There is essentially no trial data to back up this specific combination, but extrapolation from other trials with good data makes this regimen make common sense, and results in practice have been good.

Patient with poor performance status

Single agent cetuximab- Patients with poor performance status, bad kidney function, or poor blood counts may be treated with cetuximab alone.  Side effects are minimal compared to IV chemotherapy-rare allergic infusion reactions, and acne-like rash.

UPCC15309- My study, described above, allows patients with PS2.

Xeloda (capecitabine)- A single phase II study describes efficacy in a heavily pre-treated population, including patients with PS2.

Heavily pretreated patient

This is a growing problem.  Presentation with metastatic disease from SCCHN is fairly rare, as the table below shows.

from Kuperman, ASCO 2008

This means that most patients arrived at the designation “incurable” after multiple failed attempts at cure, often including induction chemotherapy, chemoradiotherapy, and repeat chemoradiotherapy with different agents.  The cancer of such patients may therefore be resistant to some or all of the therapies that we might otherwise choose.  For this reason, when chemotherapy is chosen, we prefer to give agents that have not been used before.

This was another reason behind the cap/lap trial-I don’t use capecitabine or the closely related 5-FU in either induction chemotherapy or with radiation; therefore, my patients will still be sensitive.  Lapatinib targets both EGFR and its preferred dimerization partner, HER2, so it may be very active against SCCHN.  Finally, the regimen is all-oral, and, at least in the breast cancer population where it has been previously tested, not too toxic.

When trials are not available, the basic principle of looking for active, tolerable agents that the tumor may not be resistant to still applies.  For example, capecitabine alone or methotrexate alone may be options.  Finally, phase I trials are available which allow SCCHN.

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