Cartilage invasion and or extralaryngeal spread are often considered contraindications to organ preservation approaches for patients with T4 laryngeal squamous cell carcinomas. Despite these concerns, some highly radio-responsive tumors may be cured despite large volumes or cartilage involvement. Our approach to laryngeal preservation has been to try and select the optimal patient for chemoradiation approaches using clinical response to a single cycle of neoadjuvant chemotherapy as a selection factor.5
Because most patients fear laryngectomy,11
we have typically offered this approach to all T3 or T4 patients even with tumors showing CT evidence of cartilage invasion. On rare occasions, patients with severely compromised pretreatment laryngeal function are offered primary laryngectomy because preservation of such compromised larynxes is unwarranted and improvement in function following chemoradiation is seldom complete. With a 3-year overall survival rate of 78% in patients with T4 cancers, our results strongly support the use of chemoselection as an organ preservation strategy in such patients. Hence, this may be considered as an alternative to up front surgical resection in patients with CT evidence of cartilage invasion. Compared to the best treatment arm (i.e., chemoradiation) of RTOG 91-11,1
our overall and laryngectomy-free survival rates are similar. Furthermore, our T4 subjects with CT evidence of cartilage invasion had larynx preservation rates and survival outcomes comparable to our T3 patient population (). In addition, when tumor volume was evaluated radiographically in a subset of patients, no survival differences were noted between patients with the largest and smallest tumors. This observation argues that the inherent biology of a particular tumor and its sensitivity to chemoradiation is probably more important to ultimate success of a given treatment approach than the presence of either bulky disease or cartilage invasion on imaging studies.
One other retrospective study has evaluated definitive chemoradiotherapy as treatment for high-volume T4 laryngeal cancers. The University of Chicago experience (Knab et al.)12
looked at 32 patients with untreated T4 larynx cancer, 23 of whom had large-volume tumors. All patients were treated with multiple cycles of weekly carboplatin and paclitaxel induction chemotherapy followed by treatment with concomitant paclitaxel, 5-fluorouracil, hydroxyurea, and hyperfractionated radiotherapy. With a median follow-up time of 43 months, the 4-year overall survival for the large-volume subjects was 56%, with 81% larynx preservation. At ≥ 1
year, 13% of patients were G-tube dependent, and 20% had persistent tracheostomy. These preliminary results are encouraging and consistent with our current analysis. However, a cautionary note is warranted as the Chicago experience has only been published in abstract form.
Of particular interest when comparing our results to those of Knab et al. is the difference in the use of induction chemotherapy. Our approach has been to use a single cycle of induction chemotherapy for chemoselection, whereas Knab et al. gave 6 weeks of chemotherapy prior to chemoradiation. Given that the greatest number of disease failures in our trials were in patients with distant metastases, it is interesting to speculate whether additional cycles of platinum and 5-fluorouracil (PF) as induction chemotherapy could have improved our survival outcomes, because only one third of our patients were able to receive additional adjuvant chemotherapy. Two earlier trials demonstrated an overall survival benefit with IC,13,14
and data from the MACH-NC meta-analysis showed a marginal improvement in survival (P
= .05) with IC regimens containing cisplatin and 5-FU.15
Currently, improvements in survival have been suggested with the addition of taxanes to PF in IC regimens.16,17
Recently, a study of advanced larynx cancer patients was terminated at our institution (unpublished data) after more than 50% of individuals failed to respond to chemoradiation, all of whom had greater than 50% responses to one cycle of TPF induction chemotherapy. By incorporating a more effective induction regimen, one such explanation for these local failures could be the loss of the discriminating ability of a single neoadjuvant cycle to select patients for immediate laryngectomy.
Adjuvant chemotherapy had no effect on outcome in our original UMCC 9520 study. In general, published meta-analyses demonstrate no survival benefit for its use.15,18
However, the T4 patients in this report may have obtained a benefit from additional chemotherapy following chemoradiation as none of the eight who received adjuvant chemotherapy developed distant metastases and only one had a locoregional failure. Alternatively, these patients may have had better performance status following chemoradiation, and this could be associated with better survival.19,20
We recognize that the number of patients is small, and that most patients declined adjuvant treatment due to prolonged toxicity following chemoradiation. However, it does raise the question whether patients with large-volume disease and/or cartilage invasion with good performance statuses may benefit from additional adjuvant chemotherapy.
QOL was also assessed in our analysis. Some believe that unfavorable T4 tumors with cartilage invasion are unlikely to be cured with organ preservation. Those that are cured often suffer with a dysfunctional larynx with associated aspiration and severe dysphagia, requiring permanent gastrostomy and/or tracheostomy.3
Longitudinal data regarding pretreatment factors associated with tracheostomy and feeding tube dependence were previously published from our institution. In a multivariate analysis of over 700 patients, we found that tracheostomy was a very strong predictor for g-tube dependence.21
Permanent tracheostomy rates of 3% to 7% were related to primary tumor size in the larynx, which included T4 cancers with cartilage invasion. The small percentage of T4 patients in our study that remained tracheostomy dependent was similar to the Chicago experience and that reported by the VA Laryngeal Cancer Study Group. As expected, however, the high volume T4 population had a greater number of patients requiring permanent tracheostomy compared to lower volume tumor patients. For this advanced disease population, our g-tube dependence rate is relatively low (17%). These patients, in general, had a more difficult time tolerating treatment and the majority of them received carboplatin as part of their induction and chemoradiation regimens. Similarly, none received adjuvant chemotherapy.