Mark Zafereo, M.D.

Disclaimer: The information contained within the Grand Rounds Archive is intended for use by physicians and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No warranties, either express or implied, are made with respect to accuracy, completeness or timeliness of this material. This material does not necessarily reflect the current or past opinions of the faculty of Baylor College of Medicine and should not be used as a basis for diagnosis or treatment, and is not a substitute for professional consultation and/or peer-reviewed medical literature.

I’ll begin with a case presentation of a 67-year-old gentleman, former heavy smoker and drinker who originally underwent chemoradiation therapy for a T0N2B SCC of the left neck. He developed a locoregional recurrence in the left tonsil and neck one year following treatment and underwent salvage left oropharyngeal composite resection and neck dissection. Postoperatively, he had significant dysphagia and remained partially gastrostomy tube dependent, though he was able to tolerate limited oral intake after swallowing rehabilitation. He was able to be decannulated. Unfortunately, he developed distant metastases 6 months following surgical salvage, elected for hospice care, and succumbed to his disease.

Management of patients such as this gentleman with recurrent squamous cell carcinoma of the oropharynx is certainly challenging, and today I’ll briefly discuss some of the demographics and changing patterns of recurrence with this disease, and then move onto management which includes surgical salvage, focusing on survival, functional outcomes, and reconstruction, and finally talk about some of the other treatment options.

In depth look at data from the SEER database reveals that over the last 2 decades, oropharyngeal and tongue cancer absolute numbers (illustrated by the dark lines) have increased, while other oral cavity sites and larynx are declining. And this is thought to be related to the human papillomavirus.

Management for this disease has shifted from surgery to radiotherapy with or without chemotherapy, though there are some centers that have reported good results in terms of survival and recurrence with primary surgery, especially with renewed interest with the advent of transoral laser and transoral robotic surgery, but it has yet to be agreed upon that these patients can achieve equivalent functional results.

Locoregional control has improved. Drs. Gilbert and Kagan performed a meta-analysis in 1974, reporting a range of 20-40% disease-free survival. A recent study just published online from Stanford, looked at 107 patients with oropharyngeal cancer treated with chemotherapy and IMRT. Overall survival was 83% and disease-free survival was 81% at 3 years. The decrease in locoregional failures was likely due to improved multimodality therapy, but also likely equally important is the changing demographics of the disease, including a younger patient population and increasing HPV-associated tumors in nonsmokers.

While the focus of today’s presentation is on locoregional failure, it is interesting to note, that while locoregional failure have decreased, distant failures have potentially increased. In a study of 280 oral cavity and oropharyngeal cancers in Boston, locoregional failure decreased from 26% during 1988 to 1993, to 16% during 1994 to 1999, but distant failures increased significantly from 3% to 8%. That being said, locoregional failures still remain more common than distant failures.

Reviews of the effectiveness of salvage surgery for patients with locoregionally recurrent SCCOP are rare in the literature, and there are no studies in the literature directly comparing salvage surgery with nonsurgical treatment for recurrent SCCOP. Gilbert and Kagan reviewed surgical salvage in the 1970s and found that less than 10% of tonsillar SCC were successfully surgically salvaged. In a more recent meta-analysis in 2000, Goodwin reviewed patients with recurrent pharyngeal cancer previously treated definitively with radiation, reporting only 25% recurrence-free survival at two years and 26% overall survival at 5 years. You can see from the table that patients with recurrent pharyngeal cancer who underwent surgical salvage had higher recurrence and lower survival than patients with oral cavity or laryngeal cancer.

In looking at the experience at MD Anderson Cancer Center, 3-year overall survival for surgical salvage of squamous cell carcinoma of the oropharynx was only 42%, while recurrence-free survival was even lower, at 26% at 3 years. This graph compares overall survival with salvage surgery versus those patients who were reirradiated or had palliative chemotherapy or supportive care only. While these groups are not directly comparable, as there is a selection bias, it places salvage surgery within the context of other treatment options. There was no statistically significant difference in survival among patients who had salvage surgery versus those who were reirradiated, and, as expected, 3-year survival was less than 10% for patients who had palliative chemotherapy or supportive care only.

In looking at further at the MD Anderson experience, the graph to the left illustrates overall survival coupled with disease-free interval. The patients with a disease-free interval who underwent salvage surgery, illustrated by the red line, had 3-year overall survival of almost 60%, while those who did not have a disease-free interval, illustrated by the green line, had a 3-year overall survival of less than 20%. This difference was highly significant. Even for patients who underwent nonsurgical treatment, illustrated by the purple and blue lines, the presence of a disease-free interval significantly influenced their life expectancy. Whereas, 80% of patients with a disease-free interval were alive at one year, in patients who underwent reirradiation and/or chemotherapy, only 30% were alive at one year if they had no disease-free interval. Looking at the figure to the right, at three years, over 60% surgical salvage patients with recurrent stage T1 and T2 disease were alive, as compared to a little over 20% of surgical salvage patients with recurrent T3 and T4 disease. So looking at the 14 salvage surgery patients with both a disease-free interval and small tumors for which it is possible to obtain negative surgical margins, over 70% were alive at 3 years and 45% alive at 5 years. However, this is a very select group of 14 patients, only 3% of the initial 434 patients who presented with locally recurrent oropharyngeal cancer.

So the clinical factors that are most important when deciding if patients are reasonable candidates for surgical salvage include disease-free interval and recurrent tumor size, as well as age and recurrent neck disease. In the MD Anderson study, all 10 patients who had recurrent neck disease developed a second recurrence after surgical salvage.

So it becomes clear that based on these criteria, few patients will be considered favorable salvage candidates. And in fact, while there were 41 patients who had surgical salvage in the MD Anderson study, only 14 would be considered favorable surgical candidates, which is less than 3% of the initial 434 patients who presented with recurrent oropharyngeal SCC. However, as illustrated on the previous slide, for these few patients, long-term disease control is attainable.

Others have also looked at prognostic factors with surgical salvage. Dr. Kim and others at UCLA recently studied factors which influence re-recurrence and survival in 109 patients with predominately oral cavity and oropharyngeal SCC who underwent surgical salvage and free flap reconstruction. They found that advanced T stage, advanced overall stage, and smoking status were associated with re-recurrence after salvage surgery. On multivariate analysis, tobacco status at the time of diagnosis of recurrence was the best predictor of re-recurrence following salvage surgery, with 95% of current smokers developing re-recurrence. Agra and others in Sao Paulo, Brazil also studied prognostic factors for 246 patients who underwent salvage surgery for oropharyngeal and oral cavity SCC and found advanced recurrent overall stage and disease-free interval to be most predictive of re-recurrence.

So looking at all of these studies, it appears that the clinical factors that are most important are recurrent T stage, disease-free interval, recurrent overall stage (which takes into account whether or not the patient has recurrent neck disease), and potentially smoking status.

Equally important as the decision whether or not to attempt surgical salvage is the reconstruction and rehabilitation following the ablative procedure. Because of large surgical defects in a bed of often previously irradiated tissue, oropharyngeal reconstruction and rehabilitation following salvage surgery represents one of the greatest challenges in the treatment of head and neck cancer.

Reconstruction with a regional pedicled, most commonly the pectoralis major, or microvascular free flap, is preferred over healing by secondary intention, skin grafting, or reconstruction with a local flap such as the temporalis because of concerns of insufficient tissue to close large defects, poor healing in previously irradiated tissues, and the development of scar contracture that limits the chance for any postoperative speech and swallowing rehabilitation. As Dr. Alex Osborn gave an excellent grand rounds several month ago on microvascular reconstruction of the head and neck, I’ll just briefly mention a few words about microvascular reconstruction in the context of recurrent squamous cell carcinoma of the oropharynx, and then move onto functional outcomes, which are closely tied with the ability to perform an adequate reconstruction.

This is an MD Anderson Cancer Center institutional treatment algorithm for oropharyngeal reconstruction after oncologic resection of advanced cancer. Pectoralis major pedicled flaps are reserved for patients with limited defects, poor-quality recipient vessel (either because of neck dissection or radiation history), significant medical comorbidities, and a poor prognosis. Temporalis muscle flaps are an alternative for patients with limited superior defects, such as of the tonsillar fossa or palate. Patients with more extensive defects, adequate recipient vessels, favorable medical status, and an acceptable prognosis undergo free flap reconstruction. When the mandible is not involved and the surgical defect is primarily mucosal, radial forearm fasciocutaneous free flaps offer good functional outcomes for limited defects, while anterolateral thigh free flaps are used for larger defects because they provide more soft tissue bulk to reconstruct the base of tongue, reducing the risk of long-term aspiration.

As mentioned, at MD Anderson, rectus abdominis free flaps are now less often used in oropharyngeal reconstruction because of increased donor site morbidity including pain limiting deep breathing and clearance of tracheal secretions, risk of abdominal hernia or bulge, and difficult primary closure of large donor site wounds. There is also a greater propensity for the rectus abdominis muscle to undergo atrophy after free tissue transfer, and it is difficult to perform simultaneous resection and flap harvest with two surgical teams because of the closer proximity of the primary and donor sites. But the rectus abdominis free flap remains a reasonable selection for oropharyngeal reconstruction and is used by many centers as a first-line option.

Fibula free flaps are considered for tumors involving the mandible with extension to the body or anterior mandibular arch. For patients with defects limited to the posterior mandible, including the condyle, soft tissue reconstruction alone is considered. For patients with complicated soft tissue defects in addition to posterior mandibular defects extending no farther anteriorly than the mid-body, the ALT free flap is usually selected, as tongue and pharyngeal reconstruction is simplified, trismus is rare, and dental occlusion is comparable to that with bony reconstruction when the condyle is not preserved. Patients with tumors that involve a significant amount of the anterior and posterior mandible and substantial amounts of tongue and pharyngeal mucosa ideally undergo reconstruction with a combination of free flaps, such as a fibula and a radial forearm for smaller tongue defects, or a fibula and an ALT for larger defects involving substantial amounts of the oral tongue or base of tongue.

These are a few pictorial representations of free flaps. To the left is a reconstruction of the tonsillar fossa and lateral pharyngeal wall with a radial forearm fasciocutaneous free flap in a 67-year-old male with recurrent tonsillar cancer, and to the right is a postoperative result 9 months after reconstruction. This is a limited defect, so the radial forearm flap worked well in this example. Another example, to the left, is a surgical defect in a 60-year-old woman with recurrent tonsillar fossa cancer involving the tonsillar fossa, base of tongue, and posterior mandible. The center is reconstruction of the same defect with an anterolateral thigh free flap. Bony reconstruction was not performed due to the posterior location of the defect and lower extremity peripheral vascular disease precluding harvest of the fibular flap. And finally, to the right is the postoperative result 1 month after reconstruction. So with a more extensive defect, an ALT flap is the better choice, and again bony reconstruction with a double free flap including a fibula would have been a consideration in this case if this lady had not had extensive peripheral vascular disease.

Quality of life and functional outcomes are closely tied to the ability to perform an adequate reconstruction, and there is evidence that, while re-recurrence and survival are important when evaluating the effectiveness of salvage surgery, quality of life may be an even more important concern.

Dr. List and others presented a study of principle concerns of head and neck cancer patients at the time of initial diagnosis, finding that survival far outweighed other considerations, including functional concerns such as speech and swallowing. However, it has been suggested that this balance of patient concerns shifts with recurrent disease such that pain and overall quality of life become the most important considerations, with patients perhaps becoming more realistic about chances of long-term survival, especially with recurrent oropharyngeal SCC, which has a poorer prognosis for cure than recurrence at other head and neck cancer sites, such as the oral cavity or larynx.

It’s important to evaluate functional outcomes in the context of survival as well. Drs. Netscher, Stewart and others here at Baylor studied quality of life and disease-specific functional status following microvascular reconstruction in 34 patients with advanced pharyngeal cancer and found that most patients returned to baseline functional status by 6 months after extensive surgery and surpass pretreatment thresholds by one year. Comparing this data to the median times to recurrence and disease free survivals of 8 and 9 months in studies of surgical salvage for recurrent oropharyngeal SCC, it raises the question whether surgical intervention was beneficial in terms of functional outcomes.

In the MD Anderson study, patients were evaluated at last follow-up and prior to any diagnosis of recurrence. Functionally, approximately 80% of patients were able to continue oral speech following surgical salvage, while 20% used either an electrolarynx, TEP, or writing. About one-third of patients were able to tolerate oral feeding without a feeding tube, another one-third remained partially feeding tube dependent, and one-third were completely feeding tube dependent. And of patients who had a tracheostomy, almost 90% were able to be decannulated. But, while these are very reasonable functional outcomes following large surgical resection and reconstruction, they still have to be considered in light of a 67% re-recurrence rate a median of 8 months following surgical salvage, such that most of these patients who re-recurred following surgical salvage were not able to achieve a return to their baseline functional status.

In a prospective observational study, Dr. Goodwin in Miami specifically looked at the percentage of patients who were able to achieve a return to their baseline function according to outcomes, including the FLIC, which is an acronym for “Functional Living Index for Cancer,” which is a commonly used quality of life assessment, as well as performance scales for normalcy of diet, intelligibility of speech, and eating in public. The percentages represent the percentage of patients who were able to achieve a return to their baseline function. For recurrent pharyngeal cancer, while half of patients were able to achieve return to their baseline FLIC score, only a third were able to achieve a return to their baseline diet, speech, and public eating scores.

A final factor to consider in oropharyngeal salvage surgery is cost. While economic factors are not important when considering the individual patient, societal expenditures for expensive interventions with unproven benefit will likely become increasingly scrutinized with rising costs of healthcare and limited private and government healthcare dollars. In Dr. Goodwin’s study, surgical salvage of recurrent pharyngeal cancer was more costly than surgical salvage of the other head and neck sites, with average hospital and physician charges of $86,000 per patient. Similarly, in the MD Anderson study of recurrent oropharyngeal cancer, average hospital and physician charges during the first 30 days averaged $82,500 per patient.

So, with such a large percentage of patients developing a second recurrence within 1 year of salvage surgery, it is important for patients and their families to consider all treatment options after primary treatment for recurrent SCCOP has failed.

Five-year overall survival rates as high as 20% have been reported for reirradiation in the setting of recurrent head and neck cancer, although up to one-third of patients can experience severe or fatal complications. Almost all studies in the literature include multiple head and neck sites, including two recent Radiation Therapy Oncology Group trials that included 40-50% recurrent oropharyngeal cancer patients. The first was RTOG 9610, which was the first prospective multi-institutional trial testing reirradiation plus chemotherapy consisting of 5FU and hydroxyurea for recurrent squamous cell carcinoma of the head and neck. There were 79 patients in this study with 2-year survival of only 15% and 5-year survival of 4%. In addition, 25% of patients experienced at least grade 4 acute toxicity, and there was also 8% treatment-related death. The second large RTOG study was 9911, which was another phase II prospective, multi-institutional study which accrued 105 patients who underwent reirradiation combined with cisplatin and paclitaxel. Median survival was one year, only a quarter of patients were alive at 2 years, treatment toxicity occurred in a quarter of patients, and over 10% had fatal treatment-related complications.

Although chemotherapy alone can provide palliation in patients with recurrent SCCOP, it is not a curative option. Approximately a third of patients with recurrent squamous cell carcinoma of the oropharynx have a partial response to platinum-based chemotherapy regimens, a median survival that ranges from 4 months to 6 months, and a 2-year overall survival rate that ranges from 5% to 10%. A recent, multicenter, randomized, prospective clinical trial of 442 patients with untreated recurrent or metastatic squamous cell carcinoma of the head and neck in the New England Journal of Medicine indicated that patients who received cetuximab plus platinum-fluorouracil chemotherapy had a survival benefit compared with patients who received platinum-fluorouracil chemotherapy alone with no increase in toxicity.

For patients who forego any treatment for recurrent SCCOP, the median survival can be estimated at 3-4 months. In a study of almost 200 patients with advanced or recurrent oropharyngeal cancer in Brazil who were given supportive care but no oncologic treatment secondary to advanced tumor stage, poor performance status, or patient refusal of treatment, median survival was 4 months, and only 2% of patients were alive at one year. In another study, Dr. Stell examined a case series of over 4,000 untreated head and neck cancer patients in Liverpool over a 25-year time period and found a median survival of a little over 3 months. In both studies, performance status was the best indicator of survival time.

Looking to the future, perhaps more so than clinical factors, biological markers will likely help us determine which patients are the best candidates for salvage surgery and which patients would be better suited to reirradiation and/or chemotherapy or supportive care. Last year, Dr. Agra and others in Sao Paulo, Brazil studied over 100 patients with oropharyngeal and oral cavity squamous cell carcinoma, examining both clinical factors and biological markers in association with disease-free survival after salvage surgery. What they found is that patients who had a disease-free interval of greater than one year and tumors that were endothelial growth factor receptor negative had an 80% 3-year disease-free survival, while patients who both had a disease-free interval of less than one year and EGFR positive tumors had a 3-year disease-free survival of only 20%. They also found that advanced stage recurrent tumors had a poorer prognosis, so they came up with an algorithm using all three of these factors. If patients have a disease-free interval of greater than one year, then they recommend surgery. If they have a disease-free interval of less than one year but small recurrent tumors, surgery is also recommended. If they have a disease-free interval of less than one year, a large recurrent tumor, but had an EGFR negative tumor, they still recommend surgery. But, if they do not have a significant disease-free interval and have a large recurrent tumor which is also EGFR positive, then they recommend consideration of alternative treatment. So this is an example of a treatment algorithm that could potentially be used in the future, combining both clinical and biological markers to select the best patients for salvage surgery.

So in conclusion, management of recurrent squamous cell carcinoma of the oropharynx will continue to be an important and difficult challenge for otolaryngologists and head and neck surgeons, especially with the increasing incidence of oropharyngeal cancer and a younger patient population. Patients must be carefully selected for salvage surgery, and salvage surgery should be presented to patients within the full context of treatment options, including reirradiation, palliative chemotherapy, or supportive care. Patients must have reasonable expectations for functional outcomes, but with microvascular reconstruction and ancillary services, if patients do survive their disease, they can have good functional outcomes. And finally, biomarkers, including HPV status, will likely become important prognostic factors for selecting patients for salvage surgery and represent an exciting area of research.

Case Presentation

A 67-year-old gentleman, former heavy smoker and drinker, who originally underwent chemoradiation therapy for a T0N2B SCC of the left neck. He developed a locoregional recurrence in the left tonsil and neck one year following treatment and underwent salvage left oropharyngeal composite resection and neck dissection.

Postoperatively, he had significant dysphagia and remained partially gastrostomy tube dependent, though he was able to tolerate limited oral intake after swallowing rehabilitation. He was able to be decannulated. Unfortunately, he developed distant metastases 6 months following surgical salvage, elected for hospice care, and succumbed to his disease. 

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