For a long time standard treatment approach for resectable squamous cell carcinoma of larynx was surgery with or without subsequent radiotherapy. Surgery, particulary total laryngectomy, has been associated with serious impairment of quallity of life. Between nonsurgical approaches, concurrent cisplatin based chemoradiotherapy has become a very promising treatment modality for larynx preservation. However, concurrent chemotherapy has been associated with serious toxicity. The most recent treatment approach in larynx preservation is related to taxan based induction chemotherapy

Vesna Bišof

Zoran Rakušić

English

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Coll. Antropol. 36 (2012) Suppl. 2: 231–233Review articleLarynx Preservation: Advantages and LimitationsZoran Raku{i}¹ and Vesna Bi{of²1 University of Zagreb, Zagreb University Hospital Center, Department of Oncology, Zagreb, Croatia2 University of Zagreb, Zagreb University Hospital Center, Department of Oncology, Zagreb, CroatiaA B S T R A C TFor a long time standard treatment approach for resectable squamous cell carcinoma of larynx was surgery with orwithout subsequent radiotherapy. Surgery, particulary total laryngectomy, has been associated with serious impairmentof quallity of life. Between nonsurgical approaches, concurrent cisplatin based chemoradiotherapy has become a verypromising treatment modality for larynx preservation. However, concurrent chemotherapy has been associated with seri-ous toxicity. The most recent treatment approach in larynx preservation is related to taxan based induction chemother-apy.Key words: larynx preservation, induction chemotherapy, concurrent chemoradiotherapyIntroductionUntil 1980s the method of choice for treatment of ad-vanced laryngeal cancer was total laryngectomy with orwithout postoperative radiotherapy. This modality fusedreasonable treatment results but insufficient quality oflife for operated patients. Permanent tracheotomy andloss of speech were main obstacles for generally accep-tance of this treatment approach between patients andphysicians.Based on results of concurrent and induction chemo-therapy randomised trials performed in 1990s, larynxpreservation has become a desirable treatment approachfor advanced laryngeal cancer.Combined-modality Studies in LarynxPreservationThe first randomized study demonstrated advantagein larynx preservation was published in 1991 by VeteransDepartment1. It comprised 332 patients with advancedstage laryngeal carcinoma (stage III and IV) randomizedto the induction chemotherapy cisplatin plus 5- fluorou-racil (PF) followed by surgery versus same induction che-motherapy followed by definitive radiotherapy at dose66–76 Gy. There was a significant benefit represented bylarynx preservation in 2/3 of patients treated with 3 cy-cles of induction chemotherapy and definitive radiother-apy. The overall survival did not differ between thetreatment groups.Adelstein et al.2 compared definitive radiotherapy andconcurrent PF chemoradiotherapy in the larynx preser-vation setting. At 5 years there was a benefit in rate oflarynx preservation in the group with concurrent che-moradiotherapy (26% vs 16%, p=0.03), without compro-mising the overall survival.The Radiation Therapy Oncology Group (RTOG) ran-domized trial 91–113 demonstrated significantly higherproportion of larynx preservation in concurrent cispatinbased chemoradiotherapy group than in the sequentialchemotherapy PF and radiotherapy group (at 2 years88% : 75% respectively; p=0.005). This advantage of con-current chemoradiotherapy in larynx preservation wasaccompanied with significant increase in acute toxicity,especially mucositis grade 3 and 4 (43% : 24% respec-tively). At 5 years there was no significant difference inlarynx preservation in both treatment arms. The thirdarm of the trial, radiotherapy alone, was significantly in-ferior in terms of larynx preservation rate in comparisonwith both concurrent and induction chemotherapy arm.The Groupe Oncologie Radiotherapie Tete et Cou(GORTEC) 2000–01 trial4 showed that larynx preserva-tion rate achieved with PF induction chemotherapy fol-231Received for publication October 15, 2011U:\coll-antropolo\coll-antro-(Suppl 2)-2012\44 Rakusic.vp26. studeni 2012 15:49:45Color profile: Generic CMYK printer profileComposite  150 lpi at 45 degreeslowed by radiotherapy may be improved by adding thedocetaxel to the standard induction chemotherapy proto-col PF – TPF (taxotere, cisplatin, 5 fluorouracil). Thesubgroup analysis revealed that addition of docetaxel toPF induction chemotherapy, prior to the concurrent che-moradiotherapy led to a significantly higher laryngec-tomy free survival (LFS) rate than with PF (p=0.03),without compromising survival.The authors of Phase II trial TREMPLIN5 reportedabout the contribution of epidermal growth factor recep-tor (EGFR) inhibitor, cetuximab, to larynx preservationin patients treated with TPF induction chemotherapy.This trial compared induction TPF chemotherapy fol-lowed by concurrent chemoradiotherapy with inductionTPF chemotherapy followed by concurrent cetuximabplus radiotherapy. At 3 months there was no difference inthe larynx preservation rate between treatment arms. Itwas pointed out that cetuximab plus radiotherapy wasbetter tolerated than concurrent chemoradiotherapy.Only 43% of patients were capable to receive full chemo-radiotherapy regimen, compared with 71% of patients incetuximab plus radiotherapytreatment arm.DisscusionIn spite of numerous trials performed during last twodecades there are still lot of controversies about indica-tions and treatment modalities in larynx preservationconcept. Larynx preservation consensus panel, whichmembers were leading experts in head and neck oncologyall round the world, discussed the key issues and gaverecommendations for larynx preservation trials6. Accord-ing them, T4 patients are not the best candidates for lar-ynx preservation approach due to the reduced tumor re-sponse to chemotherapy and more frequent salvagelaryngectomy in these patients. It is particularly relatedto T4 tumors which extend through the cartilage into theneck soft tissue. Such patients are not suitable for con-servative approach but rather for the initial surgery. Tu-mors exhibiting minimal cartilage invasion remain clas-sified as T3 and are eligible for larynx preservationapproach. Wide spectrum of T2 tumors are candidatesboth for conservative as well as for surgical treatment.Generally, patients with T2 disease eligible for partiallaryngectomy should be excluded from larynx preserva-tion trials. Contrary, patients with endophytic T2 tumorsor with clinical lymphadenopathy might be associatedwith lymph node involvement and extracapsular exten-sion. These patients are at high risk for regional or/anddistal relapse and should be treated with adjuvant che-moradiotherapy. Such trimodality therapy, in terms offunctional results, is worse than initial larynx preserva-tion approach.Regarding the N stage of laryngeal cancer, panelistsemphasized the increased risk of distant metastasis inpatients with N2 and N3 disease. There is also increasedrisk for extracapsular spread in these patients. Gen-erally, trials which used induction chemotherapy as ini-tial treatment, reported reduced risk for distal relapsecomparing with non-chemotherapy treatment approa-ches.The special attention was paid to the evaluation ofbaseline laryngeal dysfunction. The indicators for base-line laryngeal dysfunction include a tracheotomy, gastrictube, and recent history of pneumonia. Patients with tra-cheotomy were included in RTOG 91–11 trial3, but wereexcluded from EORTC 246547. There is still no consen-sus about this issue. The history of recent pneumonia re-quiring hospitalization represents serious toxicity andmay confuse data in toxic evaluation.The patients stratification in trials based on perfor-mance status is more acceptable option than stratifica-tion based on age alone8. In subset analysis of the Meta--analysis of chemotherapy in head and neck cancer(MACH-NC)9, patients older than 70 years of age had nobenefit of chemotherapy. Although the reasons for ex-cluding elderly from chemotherapy trials are not com-pletely transparent, panelist didn’t recommend induc-tion or concurrent chemotherapy in these settings.What has been achieved in larynx preservation ap-proach and what we can expect in the future? The sur-vival of patients with laryngeal cancer is, unfortunately,decreasing. Some experts have found possible explana-tion of decreasing survival rate of laryngeal cancer pa-tients, in overused induction chemotherapy approachwith final endpoint of spearing larynx. For sure, chemo-therapy alone is not curative, even in the best circum-stances10. Concurrent chemoradiotherapy allows higherdose intensity which has been shown to improve loco-regional control. Furthermore, long term toxicity profileof concurrent chemoradiotherapy is considerable, espe-cially mucositis. There are, generally, two frequentlymentioned factors in favor of sequential therapy. Thefirst one is that the response to the induction chemother-apy allows better selection of postinduction treatmentapproach, providing less acute and late toxicity. The sec-ond, the shrinkage of pretreatment tumor volume afteruse of induction chemotherapy improves delivery andtreatment results of Intensity Modulated Radiation The-rapy (IMRT). The last alleged advantage is doubtful. Infact, tumor shrinkage after induction chemotherapy isnot referential for radiotherapy target volume. Shrink-age of the preinduction tumor volume for radiotherapyplanning can jeopardize the treatment results. The in-duction chemotherapy delays definitive radiotherapytreatment which is substantial in the larynx preserva-tion concept. Even more, induction chemotherapy has aserious toxicity including toxic death rate in range of1–5%11. Postinduction therapy with concurrent chemora-diotherapy is more toxic and less effective that treatmentwith concurrent chemotherapy alone. Of particular con-cern is whether any toxicity associated with inductionchemotherapy will compromise the optimal administra-tion of postinduction chemotherapy and radiotherapy. Itis particularly addressed to docetaxel related myelotoxi-city12. The application of target agents like monoclonalantibodies and tyrosine kinase inhibitors in the postin-duction setting is still under investigation. For the finalZ. Raku{i} and V. Bi{of: Larynx Preservation, Coll. Antropol. 36 (2012) Suppl. 2: 231–233232U:\coll-antropolo\coll-antro-(Suppl 2)-2012\44 Rakusic.vp26. studeni 2012 15:49:45Color profile: Generic CMYK printer profileComposite  150 lpi at 45 degreesjudgment of successful laryngeal outcome, except larynxpreservation rate, the laryngectomy-free survival (LFS)is of outstanding importance. The larynx preservationapproach represents not only anatomical, but also func-tional larynx spearing procedure13,14.ConclusionSince early 1990s the larynx preservation approach ischallenging issue in the treatment of advanced laryngealcancer. Nowadays, we know that the addition of chemo-therapy to radiotherapy enables larynx preservation inpatients who are candidates for total laryngectomy. Theconcurrent chemoradiotherapy is still preferable option,comparing with induction chemotherapy, in terms of sur-vival. Due to early and late toxicity of concurrent chemo-therapy, treatment with induction chemotherapy is ac-ceptable possibility in larynx preservation approach. Theinduction chemotherapy with triplet TPF demonstratedsuperior treatment results comparing with PF. Thus, theTPF is considered as standard induction chemotherapyapproach worldwide. The most effective postinductiontreatment modality is still issue which should be recog-nized. The role of target agents in postinduction settinghas to be defined. Future trials, based on careful pre-treatment patients’ selection, have to find answers onthese questions. Radiotherapy still remains crucial partof larynx preservation approach.R E F E R E N C E S1. NO AUTHORS LISTED, DEPARTEMENT OF VETERANS AF-FAIRS LARYNGEAL CANCER STUDY GROUP, N Engl J Med, 324(24)(1991) 1685. — 2. ADELSTEIN DJ, LI Y, ADAMS GL, WAGNER H Jr,KISH JA, ENSLEY JF, SCHULLER DE, FORESTIERE AA, J Clin Oncol,21 (2003) 92, DOI: 10.1200/01.008. — 3. FORASTIERE AA, GOEPFERTH, MAORM, PAJAK TF, WEBER R, MORRISONW, GLISSON B, TROT-TI A, RIDGE JA, CHAO C, PETERS G, LEE DJ, LEAF A, ENSLEY J,COOPER J, N Engl J Med, 349(22) (2003) 2091, DOI: 10.1056/031317. —4. POINTREAU Y, GARAUD P, CHAPET S, SIRE C, TUCHAIS C, TOR-TOCHAUX J, FAIVRE S, GUERRIF S, ALFONSI M, CALAIS G, J NatlCancer Inst, 101(7) (2009) 498, DOI: 10.1093/007. — 5. LEFEBVRE JL,POINTREAU Y, ROLLAND F, ALFONSI M, BAUDOX A, SIRE C, DERAUCOURT D, BARDET E, TUCHAIS, CALAIS G AND GROUPE ON-COLOGIE TETE ET COU (GORTEC), J Clin Oncol, 27(15) abstr 6010(2009) 303s. — 6. LEFEBVRE JL, ANGKK, Int J Radiat Oncol Biol Phys,73 (2009) 1293, DOI: 10.1016/10.047. — 7. LEFEBVRE JL, ROLLAND F,TESSELAAR M, BARDET E, LEEMANS CR, GEOFFROIS L, HUPPE-RETS P, BARZAN L, DE RAUCOURT D, CHEVALIER D, LICITRA L,LUNGHI F, STUPP R, LACOMBE D, BOGAERTS J, HORIOT JC, BER-NIER J, VERMORKEN JB; EORTC HEAD AND NECK CANCER CO-OPERATIVE GROUP; EORTC RADIATION ONCOLOGY GROUP, JNatl Cancer Inst, 101(3) (2009) 142, DOI: 10.1093/460. — 8. ANG KK,Oncologist, 15(3) (2010) 25, DOI: 10.1634/S3-25. — 9. PIGNON JP,BOURHIS J, DOMENGE C, DESIGNÉ L, Lancet, 355 (2000) 949, DOI:10.1016/S0140-6736(00)90011-4. — 10. EISBRUCH A, Oncologist, 12(8)(2007) 975, DOI: 10.1634/12-8-975. — 11. POSNER M, Oncologist, 12(2007) 967, DOI: 10.1634/12-8-967. — 12. VERMORKEN JB, Oncologist,15(3) (2010) 1, DOI: 10.1634/S3-01. — 13. HORN S, OZSAHIN M, LE-FÈBVRE JL, HORIOT JC, LARTIGAU E; ON BEHALF OF AROME,Crit Rev Oncol Hematol, (2010) Epub ahead of print; DOI: 10.1016/11.008. — 14. CALAIS G, Oncologist, 15(3) (2010) 19, DOI: 10.1634/S3-30.Z. Raku{i}University of Zagreb, Zagreb University Hospital Center, Department of Oncology, Ki{pati}eva 12, 10 000 Zagreb,Croatiae-mail: zoran.rakusic1@zg.t-com.hrO^UVANJE LARINKSA: PREDNOSTI I OGRANI^ENJAS A @ E T A KDugo vremena standardno lije~enje operabilnog planocelularnog karcinoma larinksa bila je operacija uz ili bez post-operativne radioterapije. Operacija, osobito totalna laringektomija, povezana je s ozbiljnim naru{avanjem kvalitete`ivota. Izme|u nekirur{kih pristupa, konkomitantna kemoterapija sa cisplatinom postala je obe}avaju}a metoda lije-~enja u o~uvanju larinksa, ali je povezana sa zna~ajnim nuspojavama. Najsuvremenije lije~enje uznapredovalih stadijatumora, uz o~uvanje larinksa, povezano je s indukcijskom kemoterapijom taksanima.Z. Raku{i} and V. Bi{of: Larynx Preservation, Coll. Antropol. 36 (2012) Suppl. 2: 231–233233U:\coll-antropolo\coll-antro-(Suppl 2)-2012\44 Rakusic.vp26. studeni 2012 15:49:46Color profile: Generic CMYK printer profileComposite  150 lpi at 45 degrees

Larynx Preservation: Advantages and Limitations

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