an estimated 630,000 people worldwide were diagnosed with head and neck squamous cell carcinoma ( hnscc ) in 2008 , representing 6% of all malignancies and making it the 6th most common cancer [ 1 , 2 ] . in the united states , approximately 48,000 cases occurred in 2009 , with 11,300 deaths .
however , two - thirds of patients are diagnosed at a locoregional advanced stage ( iii - ivb ) , with 5-year survival rates of 30 to 60% for these patients . in the past decade , treatment of locoregional advanced hnscc has shifted from primary surgery to organ preservation with combination chemoradiotherapy ( crt ) .
the current approach attempts to achieve both organ preservation and function with outcomes superior to radiotherapy alone or surgery with postoperative radiotherapy [ 612 ] . a recent meta - analysis by pignon et al .
showed an absolute survival benefit of 6.5% at five years when chemotherapy was administered concomitantly with radiotherapy .   the mechanism for the survival benefit of crt is thought to occur via increased tumor sensitization to the cytotoxic effects of radiotherapy , while providing adjuvant treatment for potential distant metastatic disease .
however , crt has acute and long - term toxicities that can both limit treatment and increase morbidity . furthermore , although several crt regimens produce high rates of complete response at the primary site and regional neck nodes , there exists a high rate of failure to systemically eradicate micrometastases .
this is demonstrated by the later occurrence of distant metastases , which account for many cancer - specific deaths .
therefore , despite the successful use of numerous crt regimens and the development of multidisciplinary management , the prognosis of locoregional advanced hnscc remains poor . in this study , we review the outcomes of a heterogeneous cohort of patients with locoregional advanced hnscc .
all patients were treated with curative intent with a uniform crt regimen that consisted of hyperfractionated radiotherapy and concurrent cisplatin/5-fluorouracil ( 5-fu ) .
outcomes evaluated were overall survival ( os ) , locoregional control ( lrc ) , and disease - free survival ( dfs ) .
in an irb - approved study design ( greater baltimore medical center irb number 07 - 044 - 11 ) , the medical records of 105 patients with previously untreated , locoregional advanced , nonmetastatic stage iii - ivb squamous cell carcinoma of the oropharynx , hypopharynx , or larynx were reviewed .
patients with cancers of the salivary glands , sinuses , or unknown primary sites were excluded , as were patients with recurrent tumors or previous chemotherapy or radiation to the head or neck .
patients were evaluated by a head and neck surgeon , medical oncologist , radiation oncologist , dentist , speech pathologist , nurse , and social worker .
all cases were discussed prior to therapy and on a regular basis thereafter at multidisciplinary conference .
all patients underwent comprehensive head and neck exam , including laryngoscopy and triple endoscopy when necessary , and imaging assessment with chest x - ray , ct , pet / ct , or mri of the head and neck when appropriate .
all patients had a histologic diagnosis of squamous cell carcinoma and were staged according to american joint committee on cancer ( ajcc ) guidelines . when possible , tumor samples were tested for hpv-16 dna via in situ hybridization - catalyzed signal amplification as previously described .
patient demographic and clinical characteristics collected at baseline included age , gender , race , patient - reported weight loss , and karnofsky performance status ( kps ) .
in addition , history of tobacco and alcohol use was collected and categorized as follows : tobacco as nonsmoker , < 20 pack - years ( py ) , 2040 py , 4060 py , or > 60 py ; alcohol as nondrinker , < 7 drinks / week ( social ) , 714 drinks / week ( moderate ) , or > 14 drinks / week ( heavy ) . chemotherapy consisted of cisplatin ( 12  mg / m ) administered over one hour and 5-fu ( 600  mg / m ) over twenty hours , dosed for five consecutive days in an inpatient setting during weeks one and six of radiation therapy .
radiation therapy consisted of hyperfractionated doses of 125  cgy delivered twice daily for 2833 days for a total dose of 7075  gy to the primary tumor site , 60  gy to involved lymph nodes , and 50  gy to uninvolved cervical and supraclavicular lymph nodes .
patients were treated with 6  mv photon beams , opposed lateral fields with focus blocks , and neck nodes were boosted with electron beam after a cumulative dose of 40  gy .
treatment interruptions were minimized as much as possible , and a planned treatment break of one week was included after a cumulative dose of 40  gy .
mucositis severity , scored according to the world health organization ( who ) oral toxicity scale , was collected from records of patient visits to speech language pathology and clinical notes of the radiation and medical oncologists .
duration of gastrostomy tube dependence was calculated from the initiation of crt until the date of removal .
all but seven patients with clinical n2 or n3 disease at the time of presentation underwent planned neck dissection .
after treatment , patients returned for followup every 2 - 3 months in years 1 - 2 , every 36 months in years 35 , and every 612 months thereafter , or sooner in the event of a clinical concern requiring closer scrutiny .
event time distributions were estimated with the method of kaplan and meier and compared using the log - rank statistic or the proportional hazards regression model .
the simultaneous effect of two or more factors was studied using the multivariate proportional hazards model , which was reported with 95% confidence intervals ( cis ) .
os was calculated from the date of treatment initiation to the day of death or last followup .
dfs was calculated from the date of treatment initiation to the day of recurrence or death , whichever came earlier .
lrc was similarly calculated from the date of treatment initiation to the day of local or regional recurrence , whichever came first .
factors evaluated for prognostic value included age , gender , race , tumor site , histologic grade , ajcc stage , tumor stage , nodal stage , self - reported weight loss , kps , pretreatment hemoglobin , tobacco and alcohol history , and hpv status . in proportional hazards regression models ,
variables were entered as categorical effects and the hazard ratios for these factors reflect either its presence or absence .
the median followup of surviving patients was 57.6 months ( range 4.6 to 118.8 ) .
median survival was 99 months , with 3- and 5-year overall survival rates of 77 and 63% for stage iii and 72 and 58% for stage
iv . including both stages iii and iv , the 3- and 5-year os was 75 and 60% .
uni- and multivariate analyses of factors associated with survival are listed in figure 1(b ) .
on uni- and multivariate analysis , age greater than 55 , primary hypopharyngeal cancers , and advanced t3/t4 tumors were associated with decreased survival , while male gender was associated with increased survival .
on univariate analysis only , any smoking history and greater than 40 pack - year smoking history were associated with decreased survival .
hpv - positive cancers of the oropharynx were associated with slightly decreased mortality ; however , this was not statistically significant ( p = 0.3 ) .
the distribution of deaths from primary head and neck cancer and other causes is shown in table 2 .
the average time to locoregional recurrence was 13.8 months ( range 6.3 to 33.9 ) after initiation of crt .
the 3- and 5-year rates of lrc were 76 and 68% , respectively ( figure 2(a ) ) .
of the five patients who developed regional recurrences , three had undergone planned neck dissection following completion of crt .
two of these three patients had viable carcinoma identified in the ipsilateral cervical lymph nodes , while the other patient had no evidence of viable tumor identified in any lymph nodes .
the most common site of distant metastatic disease was the lungs ( n = 12 ) .
the average time to diagnosis of distant metastasis was 14.1 months ( range 3.2 to 31.9 ) after initiation of crt .
the average time to development of any recurrence or metastasis was 14.1 months ( range 3.2 to 33.9 ) after initiation of crt .
median disease - free survival was 96 months , with 3- and 5-year rates of 63 and 56% , respectively ( figure 3(a ) ) .
uni- and multivariate analyses of factors associated with dfs are listed in figure 3(b ) .
hypopharyngeal cancer and t3/t4 tumors were both significantly associated with decreased disease - free survival .
eighteen second primary malignancies ( spms ) were diagnosed in 17 patients after the completion of treatment .
the most common spm was lung ( n = 7 ) , followed by colorectal ( n = 3 ) , hnscc ( n = 2 ) , prostate ( n = 2 ) , medullary thyroid carcinoma ( n = 1 ) , chronic lymphocytic leukemia ( n = 1 ) , multiple myeloma ( n = 1 ) , and cutaneous squamous cell carcinoma ( n = 1 ) .
the average time to diagnosis of spm was 33 months ( range 3.0 to 63.2 ) .
twenty - four patients ( 36% ) had grade 3 mucositis , and 39 patients ( 59% ) had grade 4 mucositis .
the median duration of peg use was 134 days ( range 311570 ) , which included patients who died with a peg tube in place .
thirty - two of 94 patients ( 34% ) required a peg for greater than 6 months , and 10/94 patients ( 11% ) required a peg for greater than 12 months .
thirteen out of these 67 patients ( 19% ) developed a stricture , as reported previously .
seventy - one of 105 patients were nodal stage n2 or n3 , and 64 patients underwent neck dissection ( 61% ) .
of the seven patients with n2 or n3 disease who did not undergo neck dissection , two died prior to surgery , one was too ill to undergo surgery , one refused surgery , and reasons were not available for the other three patients .
this rate of viable carcinoma detected post - crt is comparable to that in the cohort of patients with oropharyngeal cancer previously reported by hillel et al . and
the use of combination chemotherapy and radiation therapy as primary treatment for locoregional advanced hnscc in medically fit patients has been well established as a treatment option in numerous trials and meta - analyses .
furthermore , altered fractionation radiotherapy with concomitant chemotherapy is a well - established treatment for locoregional advanced , nonmetastatic disease . the landmark study by brizel et al .
showed that hyperfractionated radiotherapy with cisplatin and 5-fu resulted in improved survival compared to radiation therapy alone .
therefore , we sought to review the efficacy of a uniform treatment regimen in a heterogeneous cohort with locoregional advanced hnscc .
the results of the concurrent administration of crt for 105 consecutive patients revealed favorable outcomes .
for example , two other studies reported 5-year overall survival rates of 59% and 40% , respectively , in cohorts of patients with stage iii or iv disease who received similar radiation and the same chemotherapeutic agents [ 21 , 22 ] . in another series of stage iv patients who received concurrent crt , the 5-year os was 46% .
likewise , in the study by brizel et al . , which employed similar hyperfractionated radiotherapy and concurrent cisplatin and 5-fluorouracil in the same doses as our regimen , the 3-year os was 55% and the lrc was 70% . in our cohort , 12 patients ( 11% ) developed locoregional recurrence , and 16 patients ( 15% ) developed distant metastasis .
this is comparable to other studies with similar crt regimens , which have reported locoregional recurrence in 2231% of patients and distant metastasis in 1320% of patients [ 21 , 22 ] .
the patterns of failure were approximately equal between locoregional ( n = 12 ) and distant sites ( n = 16 ) , which contrasts with several studies in which the majority of failures occur either at the primary tumor site or cervical lymph nodes [ 6 , 12 , 23 ] .
reported the results of their experience with two main treatment regimens : type 1 , intensive induction chemotherapy followed by split - course chemotherapy , or type 2 , intensive , split - course hyperfractionated chemotherapy .
they reported a 5-year lrc rate of 31 and 17% for types 1 and 2 , respectively , and a 5-year distant failure rate of 13 and 22% for types 1 and 2 .
interestingly , the patients who received induction crt were more likely to have locoregional control but were also more likely to have distant metastatic relapse .
this has prompted some to suggest the role of induction chemotherapy in treating micrometastatic disease , as other trials have shown a reduction in rates of distant metastasis with the use of induction crt . in our cohort
, there were 14 patients who presented with a primary cancer of the hypopharynx and one patient with cancers of the hypopharynx and oropharynx .
eleven of the 14 patients ( 79% ) with hypopharyngeal cancer underwent neck dissection , and 6/11 ( 55% ) had viable carcinoma ( versus 28% of the overall cohort who underwent neck dissection ) .
eight of 14 patients ( 57% ) had a recurrence , compared to 25/105 ( 24% ) in the overall cohort .
furthermore , of the eight recurrences in the hypopharynx group , seven of them presented with distant metastases .
these data reflect the poor overall survival of those with hypopharynx cancers in this cohort , which is similar to other published studies [ 2528 ] .
patients with hypopharyngeal squamous cell carcinoma may therefore need a different therapeutic approach . given the ongoing debate regarding the possibility of induction chemotherapy to better treat micrometastases , this method of crt should be considered in a direct trial against concomitant crt or perhaps a return to primary surgery with postoperative radiotherapy is warranted .
the high rate of grade 3 or 4 mucositis observed in this cohort was consistent with other reports [ 29 , 30 ] . with regard to the elective placement of peg tubes ,
this is supported by the need to maintain or minimize the weight loss associated with crt , which is between 10 to 14% [ 12 , 30 , 31 ] . in one study ,
elective versus nonelective use of peg was compared , and elective peg resulted in less weight loss and decreased length of hospitalization .
the median duration of peg use and the rate of patients that required a peg tube for longer than 6 or 12 months is similar to other studies [ 3335 ] .
furthermore , the exact duration reported may be overestimated due to the retrospective nature of this study and the inability to determine exactly when the patients no longer used the peg tube .
patients with head and neck cancer have an increased rate of second primary malignancies , estimated at 39% per year [ 2 , 36 ] .
these cancers affect the entire aerodigestive tract , are often related to smoking history , and are therefore of great significance in survivors of head and neck cancer .
consistent with these studies , the high rate of second primary lung cancer detected in our patient cohort was not unexpected and was ultimately responsible for a significant fraction of patient deaths after they were without evidence of disease of head and neck cancer . in our cohort ,
2 of 18 spm were cancers of the head and neck , similar to another cohort of patients treated with crt .
the average time to occurrence of spm was 33 months ( 2.75 years ) in our cohort , similar to other publications of 2.8 years [ 30 , 37 ] .  
in addition , treatment compliance was high , and few patients experienced unplanned treatment breaks or delays due to excessive toxicity . furthermore , long - term followup was available .
only two patients were lost to followup immediately after treatment , and all but six remaining patients had records available from a provider at our institution within the previous year .
other strengths included the utilization of a uniform crt regimen , and a thorough chart and database review and availability of the medical records of several departments . despite these strengths ,
although efforts were made to collect toxicity data , this was often unavailable and not systematically recorded in patient notes ; therefore , documentation of toxicity may have been underestimated and therefore may not be representative .
the results of this study show that the use of hyperfractionated radiotherapy with concurrent cisplatin and 5-fluorouracil remains an excellent regimen for the primary treatment of locoregional advanced head and neck cancer . however , the prognosis for patients who experience relapse remains poor , and research focused on predicting which patients will experience these events and what treatment modifications , if any , should be made in order to improve the outcomes for these patients is warranted .
lastly , the poor outcomes of patients with cancer of the hypopharynx merit consideration of ongoing research and novel therapies to lessen the mortality of this disease .
 
 objective . we reviewed a cohort of patients with previously untreated locoregional advanced head and neck squamous cell carcinoma ( hnscc ) who received a uniform chemoradiotherapy regimen . 
 methods . 
 retrospective review was performed of 105 patients with stage iii or iv hnscc treated at greater baltimore medical center from 2000 to 2007 . 
 radiation included 125  cgy twice daily for a total 70  gy to the primary site . 
 chemotherapy consisted of cisplatin ( 12  mg / m2/h ) daily for five days and 5-fluorouracil ( 600  mg / m2/20  h ) daily for five days , given with weeks one and six of radiation . 
 all but seven patients with n2 or greater disease received planned neck dissection after chemoradiotherapy . 
 primary outcomes were overall survival ( os ) , locoregional control ( lrc ) , and disease - free survival ( dfs ) . results . 
 median followup of surviving patients was 57.6 months . 
 five - year os was 60% , lrc was 68% , and dfs was 56% . predictors of increased mortality included age 55 , female gender , hypopharyngeal primary , and t3/t4 stage . 
 twelve patients developed locoregional recurrences , and 16 patients developed distant metastases . 
 eighteen second primary malignancies were diagnosed in 17 patients . 
 conclusions . 
 the crt regimen resulted in favorable outcomes . 
 however , locoregional and distant recurrences cause significant mortality and highlight the need for more effective therapies to prevent and manage these events . 
1. Introduction
2. Methods
3. Results
4. Discussion
5. Conclusions