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 Table of Contents  
Year : 2018  |  Volume : 6  |  Issue : 1  |  Page : 12-17

The long and winding road – The rocky onward march of laryngeal preservation

Departments of Surgical and Radiation Oncology (Head & Neck services), Tata Memorial Centre, Mumbai, Maharashtra, India

Date of Web Publication29-Jun-2018

Correspondence Address:
Dr. Sarbani Ghosh Laskar
Department of Radiation Oncology, Tata Memorial Hospital, Dr. Ernest Borges Road, Parel, Mumbai - 400 012, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jhnps.jhnps_45_17

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How to cite this article:
Chatterjee A, Laskar SG, Pai P, Nair D. The long and winding road – The rocky onward march of laryngeal preservation. J Head Neck Physicians Surg 2018;6:12-7

How to cite this URL:
Chatterjee A, Laskar SG, Pai P, Nair D. The long and winding road – The rocky onward march of laryngeal preservation. J Head Neck Physicians Surg [serial online] 2018 [cited 2022 Dec 5];6:12-7. Available from: https://www.jhnps.org/text.asp?2018/6/1/12/235631

  Rationale and Prelude Top

The larynx serves to perform the essential function of phonation, respiration, and airway protection at the same time. Of these, the power of coherent phonation in the form of speech is possibly the most important sociocultural function of the larynx, as it underpins our distinct identity as humans to possibly the same extent as our opposable thumbs. Consequently, the loss of voice can have devastating psychological consequences for a patient of laryngeal cancer. Traditionally, the treatment of locoregionally advanced laryngeal and hypopharyngeal cancer has entailed radical surgery, with removal of the entire larynx and the creation of a permanent tracheostomy in the neck, and as such can hardly be palatable to any patient undergoing such a procedure. Literature is replete with examples of patients who would choose the option of profoundly inferior cure rates as long as they were allowed the option of preserving the larynx.[1],[2] Indeed, the median proportion of patients willing to accept lower survival in lieu of a preserved larynx is as high as 30% in a recently published series.[3]

The profound desire of a large part of the patient population to preserve the larynx led to the investigation of alternative strategies for the treatment of laryngeal (and by extrapolation hypopharyngeal) cancers. Radical radiotherapy (RT) was explored as an option and was found to be viable as an alternative in single-institutional series, wherein it became the de facto standard of care.[4] These favorable single-institutional experiences led to exploration of the paradigm in greater detail.

Two approaches were noticed to be of particular interest. Induction chemotherapy with cisplatinum and 5-fluorouracil (5FU) (PF chemotherapy) was found to achieve favorable rates of complete response in head-and-neck squamous cell carcinoma (HNSCC).[5] Simultaneously, it was also noticed that tumors responding well to chemotherapy were also found to be sensitive to RT.[6] Thereafter, the next logical step was to test a combination of these modalities to attempt preservation of the larynx in locally advanced laryngeal cancer.

  Induction Chemotherapy Followed By Radiotherapy Top

Accordingly, Wolf et al. performed a seminal randomized trial in which 332 patients of Stage III–IV laryngeal cancer were randomized to upfront laryngectomy versus a bio-selective approach, whereby they received 2 cycles of induction PF chemotherapy followed by response assessment. Patients with either a complete response or a partial response (defined as 50% reduction in the sum of product of longest dimension of tumor and its perpendicular) received one more cycle of chemotherapy followed by definitive RT to a dose of 66–70 Gy. Patients who did not meet the above criteria were planned for salvage laryngectomy. At a median follow-up of 33 months, the 2-year survival was 68% in both arms, with the larynx being preserved in 64% of patients.[7] Importantly, a subsequent publication from the same trial data showed significantly better quality of life (QOL) scores in the patients having their larynx preserved.[8] This marked the establishment of laryngeal preservation as a paradigm in the treatment of locally advanced laryngeal cancer.

It would be of importance to carefully peruse the patient population and results of this trial. The patient population primarily consisted of patients with supraglottic tumors with clinical stage T3 and N0. Even more important is to take a look at the patterns emerging in the patients undergoing salvage laryngectomy. Rates of salvage laryngectomy were found to be higher in glottic primaries and in patients with a fixed vocal cord. Higher rates were also noted in T4 vis a vis T3 primaries and in patients where laryngeal cartilage invasion was present, with these differences achieving statistical significance. Therefore, this trial also hinted at the scenarios where laryngeal preservation was unlikely to be achieved even after favorable responses to nonsurgical therapy, underpinning the importance of careful case selection.

The successful implementation of laryngeal preservation in primary laryngeal cancers led to extension of the paradigm to hypopharyngeal cancers, where laryngeal preservation was attempted with a similar trial design.[9] There were no statistically significant differences in survival between the arms, and the 3- and 5-year estimates of retaining a functional larynx in patients treated in the induction chemotherapy arm were 42% and 35%, respectively. Understandably, the survival of patients in both the arms was poorer as compared to the Veterans' trial, given the trial population consisting mainly of locally advanced pyriform sinus cancers, which are known to have aggressive biology, with a propensity for distant metastases.

  Storm and Urge Top

Once laryngeal preservation was established initially as a paradigm, there was a felt need for more intensive local therapy. It was noticed in the Veterans' trial that a large proportion of recurrences occurred locally, with the majority of recurrences occurring within 1 year. This finding necessitated the search for a means to intensify the local therapy, which would effectively sterilize the sites of gross disease. Concurrent chemotherapy, in the form of high-dose cisplatin, had emerged as a new means of therapy intensification, and thus seemed a suitable candidate to be tried as a new modality for more effective preservation of the larynx.

Forastiere et al. designed a three-arm randomized trial (Radiation Therapy Oncology Group [RTOG] 91-11) where the prevailing standard of care, i.e., neoadjuvant chemotherapy (NACT) followed by definitive RT (with salvage surgery for nonresponders) was tested against definitive RT (to a dose of 66–70 Gy) alone and an intensified regimen consisting of similar RT with three cycles of concurrent three-weekly cisplatin chemotherapy on days 1, 22, and 43 of RT.[10] The primary end point was preservation of the larynx. However, functioning of the preserved larynx was not considered. Treatment was considered to have failed on the date laryngectomy was performed. The secondary end points analyzed were overall survival (OS), disease-free survival, local control, locoregional control, the time to distant metastasis, and laryngectomy-free survival (LFS).[10]

The patient population from this trial primarily consisted of supraglottic cancers (66%–68%). Almost half of the patients in either arm had T3 primaries with a fixed cord. The majority of patients were either node negative (50%) or had N1 disease (22%–23%). Therefore, one may notice that, apart from cord fixation, all the adverse factors mentioned in the Veterans trial were sparsely represented in RTOG 91-11. Therefore, in all probabilities, it was already being recognized that careful case selection was an integral part of any attempt at successful laryngeal preservation. The initial trial results showed a statistically significant benefit in terms of laryngeal preservation and locoregional control with concurrent chemoradiation. Definitive RT as the sole modality had the worst outcomes among all the three arms. Both the sequential and concurrent chemotherapy arms fared better in terms of disease-free survival over RT alone, possibly attributable to the lower incidence of distant metastases in these arms. However, OS did not differ across the three arms. The increased efficacy of concurrent chemoradiation came at the cost of increased acute toxicity, with Grade 3 mucosal, hematological, and pharyngo-esophageal toxicity rates exceeding 60%. However, the clear benefits of concurrent chemoradiation in terms of laryngeal preservation (with a 43% reduction in the laryngectomy rates) coupled with the high rates of locoregional control (78%) led to concurrent chemoradiation, becoming the de jure standard of care in locally advanced laryngeal cancers. In fact, the authors emphatically concluded that in most cases of laryngeal cancer, the disease can be managed without a surgical approach.

  The Twilight Top

The unequivocal nature of the advantages conferred by concurrent chemoradiation soon began to emerge as questionable. These are best illustrated in the long-term follow-up of RTOG 91-11, which was published in 2012.[11] The inadequacies of using a vague end point such as LFS, which incorporated elements of both tumor control and organ function, were laid bare and acknowledged as such by the authors. Even though chemotherapy followed by RT (CTRT) remained the most efficacious modality in achieving local control, this did not translate into a benefit in LFS or OS. Intriguingly, CTRT seemed to fare the worst in terms of long-term OS, with a statistically insignificant survival benefit emerging for the induction chemotherapy arm. An increase in noncancer deaths in the CTRT arm was postulated as a cause, with swallowing dysfunction and aspiration pneumonia cited as the possible underlying factors.[12] Two points which clearly emerged were that serious consideration needed to be given to designing end points which incorporated function and that induction chemotherapy could also be considered a serious contender as a co-existent standard of care for laryngeal preservation. This was particularly true given the increased efficacy of taxane-containing (combination of taxane + platinum and 5FU [TPF]) regimens in causing increased clinicoradiological responses and improved survival compared to RT alone.[13],[14] The same was validated in a large individual patient data meta-analysis.[15]

An additional important point which was realized was that severe late toxicity remains a significant problem encountered with CTRT,[16] which could possibly negate the advantages of intensive combined modality therapy. If CTRT were to realize its full potential in terms of converting a local control benefit into a survival advantage, a means would have to be found to render the RT less toxic.

  Three -Drug Induction Therapy for Laryngeal Preservation Top

TPF chemotherapy was tested in the specific setting of laryngeal preservation in the GORTEC 2000–2001 against PF chemotherapy.[17] The trial was special in terms of introducing a functional end point, larynx dysfunction-free survival, following the suggestions of a previous consensus panel.[18] The study showed better survival and laryngeal preservation with the TPF regimen. Indeed, TPF CTRT came to be increasingly adopted as a standard of care in Europe, whereas concurrent chemoradiation continued to be the preferred modality in North America. The time was ripe to compare these two modalities in the setting of a randomized trial.

  (Un) Decided on Paradigms Top

Long-term follow-up of a randomized trial testing the addition of neoadjuvant PF chemotherapy to definitive locoregional treatment had shown an OS benefit in inoperable patients of HNSCC, invoking optimism that this benefit would be further enhanced with the usage of TPF chemotherapy.[19] The PARADIGM and DeCIDE trials were designed to compare induction TPF followed by chemoradiation with upfront chemoradiation alone. Both trials unfortunately failed to accrue the planned number of patients. No significant differences were noticed in OS or disease-free survival.[20],[21] Moreover, serious adverse events were as high as 47% in the induction chemotherapy arm.[21]

As far as the question of laryngeal preservation is concerned, these trials did little to clear the muddied waters. Laryngeal cancer patients comprised only 14%–19% of the trial population. Nonstandard concurrent regimens (docetaxel, 5FU, carboplatin, and hydroxyurea) were used, which were more reflective of institutional experience as opposed to randomized evidence. Altered fractionation (accelerated RT and hyperfractionation) was used, despite there being no concrete evidence for a benefit of combining such fractionation with chemotherapy, as was borne out in other large randomized controlled trials.[22],[23] In retrospect, a trial design testing TPF followed by RT alone versus CTRT with concurrent 3-weekly cisplatinum would have gone much further to address the burning question at hand.

A recent randomized phase II–III trial by Ghi et al. tested induction chemotherapy versus upfront definitive treatment with CTRT or cetuximab–RT. The trial reported significantly higher OS, progression-free survival, local control, and complete responses in the induction chemotherapy arm. The study population contained hypopharyngeal cancers (18.5%–23.5%) but not laryngeal cancers. However, it provides much needed proof of a long-standing principle.[24]

  Attempts to De-Escalate Therapy and Mitigate Toxicity Top

In the decade following the publication of RTOG 91-11, intensity-modulated RT (IMRT) had emerged as a radical paradigm shift in RT, with its ability to sculpt highly conformal dose distributions around target volumes, with optimal sparing of organs at risk. It had emerged as the standard of care in the treatment of head-and-neck cancer due to its proven ability to spare the parotid gland and obviate late xerostomia.[25] In the course of realizing that noncancer deaths could be attributable to swallowing dysfunction and fatal aspiration pneumonia thereof, an attempt was made to identify the organs at risk for such toxicities. In a seminal paper, Eisbruch et al. identified the pharyngeal constrictors, supraglottic larynx, and the glottis larynx as the structures at risk and deemed them the dysphagia aspiration-related structures (DARS).[26] Dose constraints for mitigating DARS dysfunction by the same and other authors [27],[28] have been proposed. Prospective data in oropharyngeal cancer showed gratifying benefits, with minimal worsening of long-term patient-reported, observer-rated, and objective-swallowing measures as compared to pre-RT values.[29] However, extension of this paradigm to laryngeal cancer would be more challenging as the structures directly responsible for aspiration, i.e., the supraglottic and glottic larynx, are an integral part of the target volume.

Another approach which has been tried is to de-intensify the concurrent systemic therapy. The successful usage of concurrent cetuximab in locally advanced HNSCC by Bonner et al.[30] led to trial designs comparing bioRT (BioRT) with CTRT. The TREMPLIN study randomized patients responding to TPF induction chemotherapy to receive either BioRT with cetuximab or chemo-RT with 3-weekly cisplatin. The trial included a clear functional end point, larynx function preservation at 18 months posttreatment (defined as a disease-free larynx in place, without tracheotomy or feeding tube). Survival outcomes and laryngeal function preservation were similar across both arms. However, more recent data suggest that there may be a benefit in terms of laryngeal preservation with the addition of cetuximab, with better patient compliance.[31] However, reports of increased acute toxicity and a greater incidence of serious adverse events including toxic deaths also exist in literature and should incite some caution.[32] This begs testing in a large Phase III trial.

  Translation of Trial Evidence to Patterns of Care: What is Lost? Top

Following the Veterans trial and the initial results of RTOG 91-11, there was a definitive paradigm shift toward enthusiastic laryngeal preservation in advanced laryngeal cancer, especially with CTRT. This led to some unfortunate consequences. The authors noticed a decrease in the survival of locally advanced laryngeal cancer patients over time, with a concomitant increase in the usage of CTRT to treat such cancers.[33],[34] A study demonstrated a 13% increased risk of death on treatment with CTRT as compared to laryngectomy.[35] Using propensity score matching, O'Neill et al. showed an 18% increase in survival with laryngectomy.[36] More specifically, Timmermans et al. found equal survival outcomes with T3 disease and a survival outcome favoring laryngectomy over concurrent RT for T4 disease.[37]

The reasons for the differences in outcome are myriad.[38] The term “advanced laryngeal cancer” is endowed with much encompassable meaning. On the other hand, the inclusion criteria for the pivotal trials of laryngeal preservation were comparatively much more stringent. It is to be expected that large volume tumors, T4 primaries, and tumors with cord fixation are unlikely to do well in the context of laryngeal preservation. One must realize that preserving the structural integrity of the larynx alone is an inadequate end point and greater if not equal importance needs to be given to preserving laryngeal function. Allowing a dysfunctional larynx to stay in place does more harm than good and may directly contribute to patient mortality. One must also be cognizant of the fact that case selection is likely to be much more refined in an academic setting within the context of a specialized multidisciplinary head-and-neck oncology team. To achieve the same degree of decision-making finesse in wider practice would require the development of robust markers which would predict strongly regarding the success or failure of laryngeal preservation.

  What is Safe Currently and What Lies Ahead Top

As of today, laryngeal preservation is a big conundrum. However, one can come to certain limited conclusions. The ideal cases for laryngeal preservation would be nonbulky supraglottic and glottic T3N0M0 tumors with mobile vocal cords and without gross exolaryngeal extension. It is critical that one assesses the functional integrity of the larynx as regards aspiration in an objective fashion prior to attempting laryngeal preservation. Chemoradiation should be done preferably with IMRT with careful attention to DARS sparing. BioRT may be an alternative. NACT followed by IMRT in good responders is a reasonable alternative. The role of NACT remains investigational in certain special clinical scenarios such as gross soft-tissue exolaryngeal extension, without cartilage erosion. The need of the hour is to develop robust pretreatment markers on imaging (computed tomography [CT], magnetic resonance imaging, and positron emission tomography) which can predict the futility of attempting laryngeal preservation with higher specificity. There is also a need to develop robust biomarkers which can predict responses to therapy (RT and CT) and allow one to anticipate excessive toxicity. Personalized medicine remains the elusive Holy Grail.

  Tentative Steps in Personalized Medicine: Bio Selection Top

Wolf et al. published the results of a successful bio-selective approach in locally advanced laryngeal cancer, whereby patients received a single cycle of PF induction therapy. Patients with partial response were selected for definitive chemoradiation and patients with a poor response went on to undergo laryngectomy. They noticed a statistically significant difference in survival between the bioselective and the definitive chemoradiation approach.[39] Translation of this paradigm to the setting of TPF chemotherapy may lead to increased responses. However, TPF chemotherapy comes with the burden of significant severe toxicity and a small risk of mortality. Whether such an intensive approach can be used freely for what is essentially a method of triage remains highly debatable.

  Making Do for the Meantime: Published Guidelines Top

Recently published guidelines have outlined the scenarios in which laryngeal preservation may be attempted in the setting of locoregionally advanced disease.[40] Deeply infiltrative T2 lesions, T2 lesions with nodal positivity, expected poor outcomes with larynx-preserving surgeries, and nonavailability of expertise for performing larynx-preserving surgeries have all been mentioned as scenarios where organ preservation with CTRT may be used successfully. Endoscopic resections and function-preserving surgeries should be attempted in early-stage disease. Patients with extensive T3 primaries and T4a disease, especially in the setting of a nonfunctional larynx or extensive soft-tissue penetration into surrounding tissues, are deemed to be best managed with a laryngectomy rather than CTRT, to allow for better survival and QOL. In patients who desire organ preservation but are not candidates for CTRT, RT alone with the option of early effective salvage surgery is a viable option. No unequivocal recommendations have been used for the usage of NACT. In properly selected cases, CTRT remains the most effective modality for laryngeal preservation in situ. Most importantly, all patients should undergo a pretreatment assessment of voice and swallowing. Postconservation imaging and follow-up are equally important to be able to identify salvageable recurrences timely.

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  References Top

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  In this article
Rationale and Pr...
Induction Chemot...
Storm and Urge
The Twilight
Three -Drug Indu...
(Un) Decided on ...
Attempts to De-E...
Translation of T...
What is Safe Cur...
Tentative Steps ...
Making Do for th...

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