Nonsurgical Organ Preservation – Where Are We?
Year: 2025
Type: article
Abstract: Since the Veterans’ Affairs Study in 1991,[1] the Head and Neck Oncology community has been enthused with the concept of nonsurgical organ conservation. This enthusiasm also gave the patients great hope that they need not lose this important structure and that they could enjoy a near-normal life. However, in those times, organ conservation and organ and function preservation were not evaluated separately. However, after almost 30 years of this, we are still at crossroads. What is the best form of organ and function preservation in our patients? How can nonsurgical treatment approaches to laryngeal preservation reshape the future of voice restoration and patient outcomes in individuals with laryngeal and hypopharyngeal cancers while balancing functionality and quality of life? These approaches would prevent the need for a total laryngectomy (TL) and minimize the negative impact on the patient’s quality of life. According to GLOBOCAN 2022[2] data, laryngeal and hypopharyngeal cancers account for 6.7% of all cancers in India. Historically, surgery followed by radiotherapy (RT; depending on high-risk factors) was the treatment of choice. However, loss of natural voice, alteration of swallowing and olfactory functions, and permanent tracheostomy are the important morbidity of surgery. In a study by Ko et al.,[3] T3N0 laryngeal cancers had similar 5-year adjusted survival rates with RT compared to surgery. The Veterans’ Affairs Laryngeal Cancer Study[1] showed that similar 2-year survivals (68%) were achievable with neoadjuvant chemotherapy (NACT) followed by RT compared to surgery followed by RT arm in locally advanced laryngeal cancer. In this subgroup, 64% of patients preserved their larynx and were disease free. Most local recurrences occurred within 1 year of treatment completion and were salvaged successfully with surgery. Long-term follow-up data showed better quality of life including better freedom from pain, emotional well-being, and less chances of depression in the NACT arm. The EORTC 24891[4] trial with a similar design for hypopharyngeal cancers also showed that larynx preservation was possible, albeit lower than larynx (27%), with similar 10-year overall survival (OS) compared to surgery. This was then followed by the RTOG 91-11[5] which evaluated organ preservation with RT alone to concurrent chemoradiotherapy (CCRT) to NACT followed by RT in locally advanced laryngeal cancer patients. They found that 2-year intact laryngeal function was 88% and 5-year laryngectomy-free survival and distant failure were 66% and 12%, respectively, with similar OS, especially in the CCRT arm which was better than the other sequence of treatments. However, the mucosal toxicity with CCRT was significantly higher. Ten-year larynx preservation and local control rates were significantly better in the CCRT arm with similar late toxicities and OS. However, deaths unrelated to cancer treatment were highest with the CCRT arm (i.e., 30.8% vs. 20.8% – NACT arm). The first Meta-analysis of Chemotherapy in HN Cancer (2000)[6] also reported a benefit in locoregional control with concurrent chemotherapy. Hoffman et al.[7] evaluated the changes in patterns of care and survival of laryngeal cancer patients in the United States. They found that during the mid-1990s, while all other forms of head-and-neck cancers had better outcomes, survival of laryngeal cancer patients decreased, which they attributed to an increase in nonsurgical organ-preserving managements. This then prompted several investigations and more stringent criteria for selecting patients suitable for organ preservation,[8] emphasizing the need for a multidisciplinary approach in selecting the right patients. The DeLOS trial[9] evaluated the role of NACT followed by hyperfractionated RT with concomitant boost in locally advanced laryngeal and hypopharyngeal cancer patients. After 2 cycles of NACT, reassessment was done by endoscopy, repeat biopsy, and computed tomography scan. After comparisons with pretreatment disease, nonresponders (i.e., progressive or stable disease) underwent surgery followed by adjuvant RT. On the other hand, patients with clinical response (i.e., partial or complete response) received definitive CCRT. Almost 70% of patients with laryngeal and 84.3% of patients with hypopharyngeal cancer had clinical response to NACT. The goal of organ preservation was cancer control with function preservation of the larynx. Swallowing ability after treatment and tracheostomy-free breathing were assessed as a part of functional assessment. Dysphagia Grade III/IV was 1.8% at 6 months, increasing to 16% at 36 months. OS after 42 months was 56.5%. Laryngectomy-free survival was after 42 months 41.3%, with relatively rare late toxicity. The study found that patients who responded well to induction chemotherapy experienced better survival rates and functional results, while serious long-term side effects were uncommon. What is remarkable about the DeLOS II study[10] is the criteria used to assess response. After NACT-1, early response evaluation was carried out in week 4 under general anesthesia by endoscopic estimation of tumor-surface shrinkage (ETSS). If ETSS_30% was documented and verified by external review, the patient continued with per-protocol treatment. If ETSS_30% was not achieved, per-protocol treatment ended and TL was recommended. Documentation of surgical complications (after TL and neck dissection) was standardized. This may be the setting for more contemporary strategies in patient selection for improving patient-related outcomes. The advent of more potent chemotherapy agents like the taxanes enabling another strategy for nonsurgical organ preservation also merits consideration. The GORTEC (2000) trail[11] showed that triple-drug NACT regimen (docetaxel, cisplatin and 5- fluorouracil [TPF]) had better laryngeal preservation compared to double-drug regimen (Cisplatin, 5- fluorouracil), without compromising the survival. In the meta-analysis by Blanchard et al.,[12] TPF regimen had better survival. In the RTOG 90-03 trial,[13] hyperfractionation and accelerated fractionation with concomitant boost showed better locoregional control compared to standard fractionation RT in chemotherapy-ineligible patients. These altered fractionation schedules deserve consideration, though logistically posing a challenge, in view of the availability of superior RT techniques. Today, it is possible to deliver appropriate doses to the target volumes and adequately spare the organs at risk (adjacent normal structures) to spare the dysphagia aspiration-related structures in an attempt to spare the patient the morbidity of multimodality and aggressive treatment protocols.[14] Chen et al.[15] and Fang et al.[16] in their retrospective study showed excellent objective response and laryngeal preservation after adding programmed cell death protein 1 inhibitor with the nab-paclitaxel and platinum as NACT regimen. Hence, seeing the results of the retrospective studies, Chen et al.[17] conducted a prospective study, where in NACT regimen, nab-paclitaxel, cisplatin, and toripalimab combination was used. At a median follow-up of 17 months, 1-year disease-free survival was 88.0%, 1-year OS was 96.0%, and 1-year larynx preserved survival (LPS) was 92.0%, respectively, without any Grade 3–4 toxicity. Neoadjuvant treatment with docetaxel, cisplatin plus toripalimab achieved an impressive objective response rate and 1-year LPS rate with manageable toxicities. Based on the evidence available so far, it is important to consider various parameters for selection of the optimal candidate for organ preservation: patient (for example, age, smoking status, occupation, comorbidities, and reliability of follow-up), tumor (stage, site, and volume), and treatment factors (expertise, cost, and feasibility). For early-stage (T1–T2N0) glottic and hypopharyngeal cancers, a single modality of treatment is preferred, i.e., RT or organ-preserving surgery.[18] For locally advanced cancers, the treatment options depend on the laryngeal function and laryngeal cartilage involvement. For whom laryngeal function and cartilage both are intact, either CCRT or NACT may be available treatment options, depending on the extent of disease. For patients with cartilage involvement or loss of laryngeal function, the treatment of choice is laryngectomy with nodal dissection followed by appropriate and adjuvant therapy. For locally advanced hypopharyngeal cancer without a dysfunctional larynx, NACT can be prescribed in selective patients (i.e., bulky disease and gross extralaryngeal soft-tissue involvement with preserved laryngeal function without cartilage involvement). In cisplatin-ineligible patients, concurrent cetuximab[19-21] or docetaxel[22] can be used instead of RT alone. While using RT alone, altered fractionation RT is superior to the standard fractionation RT. The optimum RT technique should be IMRT with optimization of dose to DARS.[14] Although CCRT improves locoregional control and OS, allowing for organ preservation, it comes at the cost of increasing toxicity compared to RT alone.[5] Long-term toxicities of organ preservation need special attention. Organ preservation is not the same as function preservation. All these patients require active rehabilitation to maximize their speech and swallowing function after completion of treatment. The involvement of a multidisciplinary team with expertise in the treatment of these cancers is essential in determining which patients are suitable for organ preservation strategies. The availability of effective immunotherapy agents will also be a regimen to consider in future years, though access may be an issue for some time. Disclosure This material has never been published and is not currently under evaluation in any other peer-reviewed publication. Ethical approval Not applicable. Informed consent Not applicable. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
Authors: Sarbani Ghosh Laskar, Sujan Kumar Ghosh
Institutions: Homi Bhabha National Institute, Tata Memorial Hospital
Language: English
Topic: Head and Neck Cancer Studies
Subfield: Otorhinolaryngology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W4411466699