he forefront as the standard of care for organ preser-
ation. Newer strategies are being investigated and
nclude the use of induction chemotherapy before con-
omitant chemoradiotherapy and the integration of
ovel biological agents. It remains to be seen whether
uch interventions can improve on the excellent locore-
ional control shown in the landmark Intergroup trial.
2004 Elsevier Inc. All rights reserved.
rgan preservation for squamous-cell carci-noma of the larynx remains an evolving
rea of head and neck cancer research. Approxi-ately 9,500 new cases of laryngeal cancer are
xpected in the United States in 2003, and, ofhese, 60% to 65% will be glottic cancers, 30% to5% supraglottic, and 5% subglottic.1 The treat-ent strategies available to preserve the larynx
nclude conservation laryngeal surgery, radiationherapy alone, induction chemotherapy followedy radiation therapy, and concomitant chemora-iation. Quality-of-life and function evaluationre recognized as important measures of successf any organ-preservation strategy but have noteen adequately addressed in most trials to date.his article will focus on the indications for che-otherapy integrated with radiation therapy
nd, in particular, the use of concomitant chemo-adiation.
ackground
rials of induction chemotherapy were designedn the late 1970s and 1980s to test the hypothesishat reduction of tumor before local therapyould result in improved local-regional controlnd survival. Untreated squamous-cell carcinomaf the head and neck is chemosensitive with
From the Louisiana State University Health Sciences Center,tanley S. Scott Cancer Center, New Orleans, LA; and Department ofncology, Johns Hopkins University School of Medicine, Baltimore,D.
Address reprint requests to Jill Gilbert, MD, Louisiana Stateniversity Health Sciences Center, Stanley S. Scott Cancer Center,ew Orleans, LA.
reater than 50% reduction in tumor observed inpproximately 85% of patients in response to aombination of cisplatin and infusional 5-fluorou-acil (5-FU).2–7 Many randomized controlled tri-ls were performed to evaluate the role of induc-ion chemotherapy followed by surgery and/oradiation therapy (RT). These trials includedatients with primaries of the oral cavity, oro-harynx, hypopharynx, and larynx and while con-rming high response rates to induction chemo-herapy failed to show improvement in local-egional control or survival. It was apparent,owever, that chemotherapy could suppress dis-ant metastases, that response to chemotherapyas predictive of success of the subsequent ther-py, and that there was no adverse effect fromelay in surgery or RT.
These multisite trials also suggested a role fornduction chemotherapy to preserve the larynx.wo landmark trials followed: the Department ofeterans Affairs Laryngeal Cancer Study Group
VALSG) for patients with stages III and IV re-ectable larynx cancer8 and the European Orga-ization for Research and Treatment of CancerEORTC) trial for patients with stages II, III, andV resectable cancer of the hypopharynx.9 Theuestion addressed in both of these trials washether the larynx could be preserved without
eopardizing survival. Surgery was reserved foratients with inadequate response to inductionhemotherapy or persistent or recurrent local/egional disease after completion of treatment.ence, the primary endpoint of both trials was a
omparison of survival of patients randomized toreatment with sequential chemotherapy and ra-iation to that of patients in the surgery controlrm. Indeed, the results of both studies showed
hat larynx preservation was possible in a sub-
, No 2 (April), 2004: pp 167-177 167
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168 Gilbert and Forastiere
tantial percentage of patients. Survival was ei-her not significantly different or equivalent com-ared to those patients undergoing primaryurgery. A subsequent trial, Intergroup R91-11,or resectable, intermediate stage laryngeal can-er comparing 3 nonsurgical treatments to pre-erve the larynx has now been completed. We willxamine these 3 trials with emphasis on theALSG and INT R91-11 larynx studies and dis-
uss their influence on standard of care optionsnd the resulting questions that will need to beddressed in future studies.
ORTC Trial: Induction Chemotherapyn Patients With Advanced Cancer ofhe Hypopharynx
The EORTC evaluated induction chemother-py as a strategy to preserve the larynx in pa-ients with resectable T2-4, N0-1, N2a, or N2bumors of the hypopharynx. A total of 202 pa-ients were randomized to 1 of 2 treatment arms:o receive immediate surgery and postoperativeadiotherapy or to receive induction chemother-py with 5-FU and cisplatin for a maximum of 3ycles, followed by RT in complete responders.lthough the median and 3-year survival ratesere significantly different between the 2 arms
44 months and 57% for the organ preservationrm v 25 months and 43% for the surgery arm),o statistically significant survival difference wasoted at 5 years. This may be related to a delay inresentation of metastatic disease in patients re-eiving induction chemotherapy. Importantly,he 3-year estimate of organ preservation inhose patients achieving a complete response was4%.9 An ongoing EORTC follow-up trial com-ares alternating chemoradiation with inductionhemotherapy followed by RT. However, at theresent time, induction cisplatin/5-FU followedy RT remains the standard of care for patientsith hypopharyngeal cancer who desire preserva-
ion of their larynx.
ALSG: Induction Chemotherapy forrgan Preservation
n 1985, the VALSG initiated a controlled trialirectly comparing induction chemotherapy fol-owed by RT with total laryngectomy. Until re-ently, the results of this trial set the standard of
are for an organ preservation approach to laryn- 2
eal cancer. The trial compared nonsurgicalreatment with laryngectomy in patients with lo-ally advanced laryngeal cancer that required to-al laryngectomy (Fig 1). Survival was the pri-ary outcome. A total of 332 eligible patientsith untreated, locally advanced (stage III or IV)
esectable squamous cell carcinoma of the glotticr supraglottic larynx were enrolled. Patientsere randomized to receive (1) up to 3 cycles ofhemotherapy (cisplatin and 5-FU) followed bytandard fraction radiation therapy to a totalose of 66 to 76 Gy or (2) the standard of caretotal laryngectomy followed by adjuvant radio-herapy). Patients in the chemotherapy arm weressessed for response after 2 cycles of chemother-py. A third cycle of cisplatin and 5-FU was giveno those achieving a partial response (PR) (�50%eduction) or complete response (CR) at the pri-ary and no progression in the neck. Patients
hen proceeded to full-course radiation therapy.atients showing minimal response or progres-ive disease after 2 cycles of chemotherapy un-erwent immediate total laryngectomy.
With an overall tumor response rate in thenduction chemotherapy arm, 78% of patientsroceeded to radiotherapy, whereas only 16% hadlaryngectomy for inadequate response to che-otherapy and 6% died or refused further ther-
py. At 2 and 10 years of follow-up, no statisticallyignificant survival difference exists between the
igure 1. Schema of VA laryngeal trial. *Cisplatin00 mg/m2 over 20 to 30 minutes followed by 5-FU 1/m2/24 hours by continuous infusion over 120 hours.dministered in 3 cycles, 3 weeks apart. **Total lar-ngectomy or in rare instances, if supraglottic primary,orizontal partial laryngectomy. ***Seventy Gy totalose, 2.0 Gy/5 days a week for 7 weeks. ****Postsur-ical RT: 50 to 70 Gy total dose, 2.0 Gy � 5 days a weekor 5 to 7 weeks.
groups. The overall larynx preservation rate
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Organ Preservation 169
as 64%. Salvage laryngectomy was more fre-uent in patients with glottic cancers, fixed vocalords, and gross cartilage invasion, but the dif-erences were not statistically significant. Theatients at greatest risk of failure and subse-uent surgery had T4 or N2-3 disease. Fifty-sixercent of patients with T4 tumors eventuallyequired laryngectomy compared with 29% ofhose with smaller (T1-3) tumors (P � .001).attern of failure differed between the 2 groupsith more local recurrences (P � .001) and feweristant metastases (P� .001) in chemotherapy-reated patients compared with the surgeryroup.8
In a retrospective study of 332 patients (stageII, 188 patients; stage IV, 144 patients) enrolledn the VALSG trial, potential factors were eval-ated as predictive markers for response to che-otherapy, organ preservation, and survival.10
hese factors included site (glottic v supraglot-ic), stage (III v IV), T (1-3 v 4), and N (positiver negative) classification, primary tumor area,resence of extranodal extension, histologicrowth pattern, p53 expression, DNA content,nd proliferating cell nuclear antigen . In multi-ariate analysis, the only significant predictor ofesponse to chemotherapy was T stage. The riskatio of achieving response to chemotherapy for1-3 versus T4 primaries was 5.6, (95% confi-ence interval 1.5-20.8). Lower T stage (T1-3),53 overexpression, and elevated proliferatingell nuclear antigen index independently pre-icted for successful organ preservation, al-hough supraglottic site and aggressive growthattern were associated factors on univariatenalysis. Predictors of decreased survival on uni-ariate analysis were primary tumor area (�4m2, 4-9 cm2, 10-14 cm2, or �15 cm2) and positivelinical nodal status (P � .013, .014, respec-ively). However, on multivariate analysis, no fac-ors significantly predicted for survival for pa-ients in the organ-preservation arm.11
The Veterans Administration trial includeduality of life studies and assessments of functionelative to communication, swallowing, and eat-ng. Patients who had a preserved larynx hadignificantly better scores on communicationvaluations at 6-, 12-, and 24-month time pointsfter randomization. However, the majority ofaryngectomy patients used an artificial electro-arynx to aid with communication (55%) or tra-
heoesophageal speech (31%). Only a small per- q
entage of patients randomized to laryngectomyemained nonvocal. There were no significantifferences in swallowing function.12
These results formed the basis for a new stan-ard of care for patients desiring preservation ofheir larynx: induction chemotherapy (cisplatinnd infusional 5-FU) followed by RT for chemo-herapy responders reserving laryngectomy foralvage or those with recurrent or persistent dis-ase. Although this was quickly incorporated intolinical practice, the precise contribution of che-otherapy was unclear and many argued that the
ame rate of larynx preservation could bechieved with RT alone and spare patients che-otherapy-related toxicity. No prospective trials
ave directly compared radiotherapy with pri-ary surgical management.Radiotherapy as definitive treatment is used in
he United States for treatment of selected pa-ients with T3 or T4 N0-1 cancers with favorableharacteristics. Single-institution retrospectivease series report 5-year local control rates rang-ng from 48% to 62% depending on site andtage.13–16 In Canada and Great Britain, radio-herapy alone is the standard initial managementf advanced laryngeal cancer reserving surgeryor salvage.17 Local control rates at 5 years for3-4 N0 cancers range from 45% to 56%.17–20
oor local control after primary radiotherapy andhe need for subsequent laryngectomy is associ-ted with high-volume T4 disease including soft-issue invasion, cartilage invasion, need for tra-heotomy, extensive involvement of the pre-piglottic space, and base of tongue involvement.rospective evaluations of patients with laryngealancer undergoing magnetic resonance imagingefore definitive radiation therapy have shownhat cartilage invasion significantly predicts forocoregional recurrence.21,22
To directly address the question of the role ofhemotherapy when added to RT, a prospective,andomized trial evaluating 3 nonsurgical treat-ents for advanced laryngeal cancer wasounted, Intergroup trial R91-11. The adminis-
ration of cisplatin concurrent with radiotherapys known to enhance radiation cell kill offeringhe possibility of improved local-regional controlnd laryngeal preservation compared with theequential administration of these modalities.he trial was designed to determine the preciseontribution of chemotherapy and optimal se-
uencing of chemotherapy and RT (Fig 2).
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170 Gilbert and Forastiere
oncomitant Chemoradiotherapy
nly 1 prospective randomized trial evaluatingoncomitant chemoradiotherapy to preserve thearynx that is limited to patients with laryngealancer has been completed. The results will soone published.23 However, many positive mixed-ite trials of this approach versus radiotherapylone have been performed in patients with lo-ally advanced disease. These studies have shownmproved locoregional control, disease-free sur-ival, and survival.24–29
Although these trials showed significant im-rovements in the aforementioned endpoints,oxicity was significantly increased with concom-tant treatment. Novel chemotherapy schedules,uch as daily low-dose cisplatin, have also shownhat such an approach is feasible without a sig-ificant increase in toxicity.24
Intergroup R91-11: Comparison ofInduction Chemotherapy Followed by RT,Concomitant Chemoradiation, and RTAloneThe Intergroup trial R91-11 represents the
rst prospective randomized trial specifically ad-ressing the role of concomitant chemoradiother-py to preserve the larynx in patients with laryn-eal cancer. The primary objective of the trialas to compare the rates of laryngeal preserva-
igure 2. Schema R91-11. Arm 1: cisplatin 100 mg/m2
ver 20 to 30 minutes followed by 5-FU 1 g/m2/24 hoursy continuous infusion over 120 hours. Administered incycles, 3 weeks apart. Arm 2: Cisplatin 100 mg/m2
ver 20 to 30 minutes administered on days 1, 22, and3 of RT. *70 Gy total dose, 2.0 Gy/5 days a week for 7eeks. RT for arm 1 will begin 3 weeks after the startf the third chemotherapy cycle or 2 to 3 weeks afterurgery as applicable. **Postsurgical RT: 50 to 70 Gyotal dose, 2.0 Gy � 5 days a week for 5 to 7 weeks. P,isplatin; F, 5-FU.
ion between 3 treatments: induction chemother- 5
py (per the VALSG trial), concomitant chemo-adiation, and RT alone. Eligible patientsncluded those with previously untreated, resect-ble squamous-cell carcinoma of the glottic andupraglottic larynx, stages III and IV. Excludedere patients with T1 primaries and those withigh-volume T4 primaries (tumor penetratinghrough cartilage into soft tissue or invadingore than 1 cm into the base of tongue). A total
f 518 eligible patients were randomized to 1 of 3reatments. Arm A consisted of up to 3 cycles ofnduction cisplatin and 5-FU followed by radia-ion therapy. This arm was identical to theALSG trial induction chemotherapy regimen.esponse was assessed after 2 cycles of chemo-
herapy; a partial response at the primary and norogression in the neck was required to receive ahird cycle of cisplatin/5-FU followed by RT. Arm
consisted of concomitant chemoradiotherapysing cisplatin 100 mg/m2 on days 1, 22, and 43uring radiation. Arm C consisted of radiationherapy alone. Radiation dose and schedule wasdentical for all 3 treatments: standard fraction-tion, 2.0 Gy/fx, and total dose 70 Gy/7 weeks.atients with N2 or N3 disease on initial stagingnderwent elective neck dissection 6 to 8 weeksfter completion of radiation therapy. Surgeryas reserved for salvage of patients in all 3 treat-ent arms with biopsy-proven persistent disease
t completion of RT or recurrence.This was a study of patients with intermediate
tage disease. Seventy-nine percent of enrolledatients had T3 primary tumors, whereas only0% were T4 and 72% had N0-1 neck disease;5% were classified as stage III and 35% as stageV (Table 1). Several key findings have resultedrom this study. At 2 years, significantly moreatients receiving concomitant chemoradiationad a preserved larynx (88%) compared withhose receiving induction chemotherapy (75%,
� .0047) or RT alone (70%, P � .00012).imilarly, local-regional control was significantlyetter for patients treated with concomitant che-oradiotherapy (78%) versus induction chemo-
herapy (61%, P � .0031) or versus radiationlone (56%, P � .000020). Chemotherapy sup-ressed distant metastases, whether given as in-uction or concomitantly with radiation therapy.he 2-year distant failure rates were 9%, 8%, and6%, for the 3 treatments, respectively. Thereas no statistically significant difference in 2- and
-year survival estimates. The 2-year survival
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Organ Preservation 171
ate was excellent at 76%. Salvage laryngectomyas performed on 28% of patients in arm A, 16%f patients in arm B, and 31% in arm C (P �002). Survival of patients who underwent salvageotal laryngectomy did not differ by treatment69% for arm A, 71% for arm B, and 76% for arm, P � .73).23
Self-report questionnaires on speech and swal-owing were available from greater than 70% ofatients on each arm of the study. Several impor-ant conclusions can be made at this time. First,o significant difference in self-assessment ofpeech was noted between the 3 arms at 12 and4 months of follow-up. Second, with regard towallowing function, patients in arm B showedignificantly impaired swallowing in comparisono arm A (P � .0041). Swallowing function in arm
did not significantly differ from patients in thether 2 treatment arms. No difference in theercentage of patients reporting difficulty swal-owing was evident at 2 years (16%, 15%, and4%, respectively).23
In summary, several important points should
able 1. Comparison of Landmark Trials
VALSG R 91-11
Number ofpatients
332 547166 PF3RT PF3RT166 S3RT RT � P
RTSites Supraglottic 63% Supraglottic 69%
Glottic 37% Glottic 31%Stage III 56% III 65%
IV 44% IV 35%Incidence of
Grade 3 andGrade 4Toxicities(acute andlate)
81%82%61%
LocoregionalControl
2 year 80% 2 year† 64%93% 80%
58%Organ
Preservation2 year 67% 2 year† 72%
88%67%
OverallSurvival
2 year 68% 2 year* 76%68% 74%
75%
bbreviations: PF, cisplatin and 5-FU; RT, radiation therapy;, surgery.No statistically significant difference between the arms.Statistically significant difference between arm B and arm Ar arm C.
e emphasized. Firstly, the trial sets a new stan- p
ard of care for achieving larynx preservation:oncomitant chemoradiation using standard frac-ionation and high-dose cisplatin. Chemotherapydded to RT substantially increases the incidencef severe acute toxicity, whereas late toxicityates appear about the same. Acute toxicity fromhemotherapy included bone marrow depressionnd when given concomitant with RT, enhancedn-field mucosal and skin toxicities. This necessi-ates aggressive supportive care to maintain ad-quate caloric intake and hydration and to pro-ide pain management.
The primary question of which treatmenttrategy was best to achieve larynx preservationas answered. A second important outcome was
he observation that the addition of inductionhemotherapy was not better than RT alone forchieving organ preservation for these patientsith intermediate stage disease. Although a de-rease in distant metastatic rate and increase inisease-free survival were observed for the com-arisons of induction chemotherapy followed byT to RT alone, survival, local-regional control,nd rate of salvage laryngectomy were not differ-nt. Thus, for patients unable to tolerate thedded toxicity of concomitant chemoradiation,T alone should be recommended. The risk ofeeding laryngectomy within 2 years is approxi-ately 30% compared with half that or about
5% if treated with concomitant RT and cispla-in.
Comparisons of the VALSG trial and R91-11hould be made cautiously as the VA trial in-luded more advanced (T4) patients and moreith glottic cancer. The results of the 2 identical
nduction chemotherapy arms indicate a higherrgan preservation rate (64% v 72%) and 2-yearurvival (68% v 76%) for patients enrolled in91-11. This likely reflects the difference in pa-
ient characteristics. The response to chemother-py was identical, 85% in both trials after 2 cy-les. Thus, in many respects, the outcomes fromrm 1 (induction) of the R91-11 trial essentiallyonfirm those of the VALSG induction arm.
Salvage Laryngectomyhe morbidity of salvage laryngectomy for pa-
ients who have failed an organ-preservation ap-roach is an area of active investigation. Goodwinublished a comprehensive review of the compli-ations of salvage laryngectomy reported in 7
30
ublished series totaling 718 patients. The ma-
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172 Gilbert and Forastiere
or complication rate was 27% (range 5%-48%).assler et al31 reported the results of a retrospec-ive survey of the incidence and risk factors forajor wound complications (MWC) in 18 pa-
ients requiring salvage laryngectomy after anrgan preservation approach. They noted MWCn 61% of patients; 50% had a pharyngocutaneousstula. This analysis included 96 patients en-olled in protocols evaluating induction chemo-herapy (cisplatin or carboplatin combined with-FU) followed by standard fractionation RT.he total radiation dose ranged from 66 to 74 Gynd 50 to 74 Gy to the primary tumor and theeck, respectively. Complications included pha-yngocutaneous fistula, wound breakdown andecrosis, wound infection, pedicle flap necrosis,steonecrosis, and chyle fistula. In this small se-ies, the MWC rate was substantially higher77%) for those patients receiving salvage laryn-ectomy within 12 months of completing therapyersus greater than 12 months after completionf initial therapy (20%). Furthermore, a trendoward decreased rate of MWC was noted inatients who did not require opening of the phar-nx.31
These data suggest a high incidence of MWCn patients undergoing laryngectomy after induc-ion chemotherapy and definitive radiation ther-py. The question of whether similar rates ofWC are seen after concomitant chemoradio-
herapy has recently been examined. In a retro-pective review of 100 patients treated in a phaseII trial comparing radiotherapy alone versusoncomitant, platinum-based chemoradiotherapyor advanced stage head and neck cancer, approx-mately 54% of patients underwent subsequentlanned neck dissection or salvage surgery. Pa-ients were evaluated for clinical response aftereceiving 55 Gy RT. Those showing at least a PRontinued treatment to a total radiotherapy dosef 68 to 72 Gy. The number of surgical proce-ures was similar in the 2 treatment groups. Forll surgical procedures, the MWC rate was 12%n the radiation only arm and 12% in the chemo-adiotherapy arm. On evaluation of wound com-lications separately for planned neck dissectionsnd for salvage surgery, no significant differenceas found in either major or minor wound com-lications between the treatment groups. Theotal rate of surgical complications (all types) inhe radiotherapy versus chemoradiotherapy arm
as not significant at 58% versus 64%, respec- r
ively. However, the complication rate was signif-cantly higher in patients undergoing surgicalalvage (60%) versus those who had a plannedeck dissection (31%), regardless of initial treat-ent arm.32
An evaluation of the incidence of morbidity,ortality, and disease control for patients requir-
ng salvage laryngectomy after an organ preser-ation approach in R 91-11 has recently beenompleted. Salvage laryngectomy was required in29 patients (25%): 48 (28%) of patients receiv-ng induction chemotherapy (arm A), 27 (16%)eceiving concurrent RT and cisplatin (arm B),nd 54 (31%) in the radiation therapy alonereatment group (arm C) (p�0.002). The indica-ions for laryngectomy in 95% of patients wereack of response to induction treatment, persis-ent disease at completion of RT or recurrence,hereas 5% required laryngectomy because of
aryngeal necrosis or dysfunction. The total inci-ence of complications (major and minor) was8%, 59%, and 52%, respectively, for the 3 treat-ent groups. Importantly, in those patients re-
uiring salvage laryngectomy for recurrence, ne-rosis, or dysfunction, the most frequentomplication was pharyngocutaneous fistula,hich ranged from 15% (arm C) to 30% (arm B),hich compares favorably with historical con-
rols. The incidence of surgical complications wasot related to the time interval between comple-ion of initial therapy and laryngectomy. Afteralvage surgery, local-regional control was ob-ained in 74% of patients who had received che-otherapy (arms A and B) and 90% of patients
reated with RT alone (arm C). An analysis ofatients surviving at least 1 year after salvagearyngectomy showed a significant decrease inurvival compared with those who did not requirearyngectomy (P � .02). However, there was noignificant difference in disease-free or overallurvival when analyzed as a function of initialreatment arm.33
These results highlight the concept that pa-ients who require salvage laryngectomy repre-ent a subgroup with a worse prognosis, regard-ess of initial organ preservation treatment.dditionally, in those patients who required sal-age laryngectomy, the incidence of postopera-ive complications was independent of the timingf surgery (in contrast to other reports for induc-ion chemotherapy protocols), and complication
ates mirror historical controls.
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Organ Preservation 173
Controversiesoncomitant chemoradiotherapy as an organ-reservation strategy has not been extensivelyvaluated for its role in patients with cartilagenvasion (T4 disease). The characteristics of la-yngeal tumors that are considered favorable ornfavorable with respect to achieving local con-rol when treated with radiotherapy alone haveeen empirically defined. Unfavorable character-stics associated with a high rate of surgical sal-age include cartilage or soft-tissue invasion, ex-ension into the hypopharynx or oropharynx, basef tongue involvement, pre-epiglottic space in-olvement, and infiltrative rather than exophyticrowth pattern. Most of these unfavorable char-cteristics define high-volume T4 disease. Pa-ients with favorable tumor characteristics areften selected for treatment with radiotherapylone and therefore may not be comparable toatients for whom surgery is recommended. Thisractice has resulted in reports of estimated-year local control rates for radiation therapylone of approximately 62% for low volume oravorable T4 glottic cancers and 48% for selectedupraglottic cancers.21–22,34–38 These rates areomparable to those reported using surgery andostoperative radiotherapy or induction chemo-herapy followed by radiotherapy.13–20
Although the data do not support the routinese of organ preservation in all patients with T4isease, several important points must be empha-ized. Firstly, historical data using radiationlone stems from trials performed largely in the970s and 1980s. Advances in radiation therapy,ncluding intensity-modulated RT and novel ra-iation schedules, may prove superior to standardractionation, but phase III trials directly com-aring surgery with RT would be required. TheTOG 9003 phase III randomized study of hy-erfractionation and 2 variants of acceleratedractionation to standard fractionation radiother-py for squamous cell carcinoma of the head andeck showed that locoregional control is im-roved with concomitant boost and bid fraction-tion without an increase in survival. Approxi-ately 30% of patients in each arm showed T4
isease, although primary site of disease was notimited to the larynx.39 A definitive trial compar-ng altered fractionation RT versus chemoradio-herapy (standard fractionation) is unlikely to be
ndertaken as intensifying radiation therapy o
lone would not be predicted to result in in-reased survival. Altered fractionation with con-omitant chemotherapy or altered method ofhemotherapy administration, however, may be aromising option for a poor prognosis subset ofatients. Samant et al40 treated 135 patients with4 laryngeal disease with intra-arterial infusionsf cisplatin and concomitant RT to a totallanned dose of 66 to 74 Gy. Forty-five of the 135atients had clinical or radiographic evidence ofone and/or cartilage invasion. No significant dif-erence in complete response rate or 2-year over-ll survival was noted in the group with bonend/or cartilage invasion versus the group with-ut these findings.40
Secondly, although high-volume T4 diseasetumor through cartilage into soft tissue or su-raglottic primary extending into the base of theongue) was excluded from R 91-11, a subset ofhese patients may be eligible for organ preser-ation. If tumor extends through the organ intooft tissue (eg, glottic T4 disease), then organreservation would likely be futile because thergan has been largely destroyed. However, ifata are extrapolated from multiple positive ran-omized trials in patients with oropharyngealrimaries, then patients with large supraglotticumors may be successfully treated with concom-tant chemoradiotherapy. Further study needs toe undertaken on this patient population at highisk of treatment failure because newer treat-ent strategies may allow an organ-preservation
pproach. Randomized prospective trials in pa-ients with historically “adverse” features willeed to be conducted to best answer these re-aining questions.In summary, some T4 disease (T4 supraglottic
isease with extension into base of tongue) mayltimately benefit from a concomitant chemora-iotherapy approach. However, in glottic diseasehat has penetrated cartilage into soft tissue, theoncept of “organ preservation” becomes irrele-ant because the organ has already been de-troyed by the disease. These patients warrant aurgical approach. However, if cartilage invasionoes not penetrate into soft tissue, then organreservation may still be attempted. It is impor-ant to realize that a stage migration of tumorsikely exists with newer imaging modalities thatdentify early, small-volume cartilage invasion,hich may still be excellent candidates for an
rgan-preservation approach.
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Recommendationshe following are recommendations for organreservation:
. Glottic primaryA. T2 N0: Single-modality therapy (surgery or
radiation therapy); await results of RTOG95-12, which randomized patients to hyper-fractionation versus conventional fraction-ation in T2 SCC of the vocal cord
B. T2 N�: concomitant chemoradiotherapy;recommend standard fractionation RT tototal dose 70 Gy with cisplatin 100 mg/m2
given on days 1, 22, and 43; alternatively,single modality standard fractionation RTfor select T2N1 patients
C. T3 N0: concomitant chemoradiotherapy;recommend standard fractionation RT tototal dose 70 Gy with cisplatin 100 mg/m2
given on days 1, 22, and 43; alternatively,single-modality standard fractionation RT
D. T3N�: concomitant chemoradiotherapy;recommend standard fractionation RT tototal dose 70 Gy with cisplatin 100 mg/m2
given on days 1, 22, and 43; alternatively,single modality standard fractionation RTfor select T3N1 patients unable to toleratechemoradiation
E. T4 N0 or N� with penetration throughcartilage into soft tissue: surgery followedby standard fractionation radiation therapy
F. T4N0 or N� without cartilage invasioninto soft tissue: concomitant chemoradio-therapy; recommend standard fraction-ation RT to total dose 70 Gy with cisplatin100 mg/m2 given on days 1, 22, and 43;alternatively, single-modality standardfractionation RT for select T4N0 or N1patients
. Supraglottic primaryA. T2N0: Single-modality therapy (surgery or
recommend standard fractionation RT tototal dose 70 Gy with cisplatin 100 mg/m2
given on days 1, 22, and 43; alternatively,single-modality standard fractionation RTfor select T2N1 patients
C. T3N0: concomitant chemoradiotherapy;recommend standard fractionation RT tototal dose 70 Gy with cisplatin 100 mg/m2
given on days 1, 22, and 43; alternatively, t
single-modality standard fractionation RTfor patients unable to tolerate chemoradia-tion
D. T3N�: concomitant chemoradiotherapy;recommend standard fractionation RT tototal dose 70 Gy with cisplatin 100 mg/m2
given on days 1, 22, and 43; alternatively,single-modality standard fractionation RTfor select T3N1 patients for patients un-able to tolerate chemoradiation
E. T4N0 with extension into base of tongue:historically, treated with surgery followedby radiation therapy. However, if data wereextrapolated from the experience in oro-pharyngeal cancer, concomitant chemora-diotherapy would be a reasonable option;needs to be further evaluated in random-ized clinical trials
F. T4N0 or N� without extension into base oftongue: concomitant chemoradiotherapy;recommend standard fractionation RT tototal dose 70 Gy with cisplatin 100 mg/m2
given on days 1, 22, and 43; alternatively,single-modality standard fractionation RTfor select T4N1 patients
G. T4N0 or N� with cartilage invasion intosoft tissue: surgery followed by standardfractionation radiation therapy
“Select patients” would include patients withgood risk features” including minimal to no car-ilage invasion, no extension into hypopharynx orropharynx, no pre-epiglottic space involvement,nd exophytic growth pattern. R91-11 showedhat patients who required salvage laryngectomyhowed a significantly decreased overall survivalut that the survival decrease was independent ofreatment arm.
uture Directions
he high rate of larynx preservation (88% at 2ears, 85% estimated at 5 years) achieved withT and concomitant cisplatin in R91-11 means
hat future trials will need to address other ques-ions. To show further improvement in the lar-nx, preservation rate would require prohibitiveumbers of patients. Alternatively, importantutcomes including improved survival rate andeduction of acute and late toxicity should beursued. One investigational approach to achieve
hese goals is the addition of induction chemo-
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Organ Preservation 175
herapy to concurrent chemoradiation. An East-rn Cooperative Oncology Group trial of thisesign (E2399) is in progress. In this phase IIrial, patients with resectable stage III or IVancer of the larynx or oropharynx (T2-T4) re-eive carboplatin area under the curve 6 andaclitaxel 175 mg/m2 over 3 hours repeated onay 22 for a total of 2 cycles. Patients showing ateast a partial response at the primary site re-eive weekly paclitaxel concomitant with stan-ard fractionation radiation therapy. The choicef paclitaxel resides in its established activity inatients with recurrent head and neck cancer andn its radiosensitizing properties in combined mo-ality regimens in the primary management ofewly diagnosed patients. Phase II trials of singlegent paclitaxel or docetaxel in patients withecurrent squamous cell cancer of the head andeck show response rates in the 30% to 40%ange, exceeding the activity of most other singlegents tested in this disease.41,42 The acceptableoxicity profile of the taxanes in combination withT may provide an advantage over high dose
isplatin. In this design, induction chemotherapyay have its principal effect on suppressing dis-
ant metastases, whereas low-dose weekly, radio-ensitizing chemotherapy with RT improves lo-al-regional control. In theory, these maneuvershould translate to improved survival.
The primary goals of E2399 include the assess-ent of organ preservation rate, determination
f the feasibility and toxicity of the regimen, andvaluation of the utility of pre- and posttreat-ent objective and self-report instruments to as-
ess swallowing ability and voice quality. Second-ry endpoints include disease-free survival,attern of failure, objective tumor response rate,nd quality of life evaluation. A preliminary re-ort of baseline swallowing function in 60 pa-ients showed that on self-report 78% of patientsad normal swallowing function. However, only5% had normal swallowing by objective mea-urement with a modified barium swallow. As-essment of physiologic swallowing function re-ealed that 55% of patients had mildropharyngeal dysphagia.43 Serial posttreatmentvaluation of these endpoints out to 24 monthsrom completing treatment is ongoing.
Although concomitant chemoradiotherapyepresents the new standard of care for organreservation, other strategies are under investi-
ation to improve survival rates such as the in-
orporation of novel targeted therapies and thentegration of new imaging modalities into or-an-preservation approaches. Several ongoingrials incorporate monoclonal antibodies or smallolecules that target the epidermal growth fac-
or receptor into combined modality regimens.reliminary data from these studies should bevailable in the near future. Well-designed ran-omized controlled trials incorporating theseew agents and the evaluation of biologic end-oints need to be prospectively evaluated. Para-igms will need to be established for evaluatinguality of life and functional outcomes as moreatients undergo treatments to preserve organunction and are long-term survivors with an in-act larynx.
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