Selection for CRT versus early salvage surgery by using the response to IC is an approach to organ preservation that has shown an improved outcome in advanced larynx cancer.19
In the present study, a similar treatment strategy was used in patients with advanced SCCOP. The organ preservation, DSS, and OS rates compare favorably with historical controls.28,29
Our results are comparable to those obtained by the Southwest Oncology Group trial of 37 patients with stage III to IV base-of-tongue squamous cell carcinoma who were treated with two cycles of cisplatin and fluorouracil that was followed by CRT for those who responded to IC.30
Many trials include multiple sites in the head and neck; however, because site affects outcome, it is important to analyze sites separately. For example, in the Southwest Oncology Group trial,30
base-of-tongue tumors fared better than hypopharynx tumors. Similarly, patients with stage III to IV squamous cell carcinoma of the oral cavity who were treated with the UMCC 9921 protocol had poorer OS, poorer organ preservation,31
and a lower rate of functional swallowing than oropharynx patients who were treated identically. Likewise, patients on UMCC 9921 with base-of-tongue tumors had poorer survival compared with those who had tonsillar tumors on UMCC 9921 or compared with those who had stage III or IV larynx cancers treated on the similar UMCC protocol (9520).19
Other factors that vary by site also affect outcome. In particular, HPV plays an important role in SCCOP.5,6
By using the AttoSense HPV Test (licensed to SensiGen, Ann Arbor, MI) to identify and quantify high-risk HPV viral copy number, we found that 69% of tonsil and 62% of base-of-tongue tumors contained HPV16. High HPV copy number in the pretreatment biopsy was associated strongly with response to IC and CRT and with improved survival. It is not known why patients with HPV-positive tumors fare better in nearly all studies published to date.5,32-35
One explanation is the immune response to viral antigens.36
Another possibility is that the Rb and p53 pathways are compromised but remain intact to retain some function, such that, under the pressure of chemotherapy or radiotherapy, p53-mediated apoptotic pathways may still function. However, much work is needed to test these possibilities.
The use of carboplatin in the metastatic or recurrent setting has inferior response results when compared with cisplatin.37
Although our study of previously untreated tumors was not designed to compare efficacy of the two chemotherapeutic agents, it appears that carboplatin was not inferior to cisplatin in terms of response to IC or organ preservation. Furthermore, during CRT, substitution of carboplatin for cisplatin helped to improve compliance rates with chemotherapy. Seventy percent of our patients received all three cycles of chemotherapy compared with similar regimens that used only cisplatin, in which compliance rates were 50% to 60%.38,39
UMCC 9921 included planned neck dissections for patients with neck nodes greater than 3 cm, but all were negative for residual tumor. On the basis of this and on the value of PET imaging to assess CRT responses in multiple tumor types,40-43
our practice evolved to monitor the neck at 8 to 10 weeks after CRT with computed tomography/PET. PET scans, however, were not required by the protocol. Patients with N0 disease in our study had worse outcome than those with N-positive disease. This was independent of HPV and may be due to a greater incidence of current smokers in the N0 group.
A survival benefit for adjuvant chemotherapy has never been documented.44,45
In UMCC 9921, adjuvant paclitaxel increased permanent sensory neuropathy, was difficult to administer because of cumulative toxicity after cisplatin, and did not result in any survival benefit. Hence, adjuvant paclitaxel was not effective in this design.
In contrast to our expectations from UMCC studies that involved the larynx, salvage surgery for SCCOP was ineffective in all who failed CRT and in five of nine nonresponders to IC. Whether nonresponders to IC would have fared better if they received CRT instead of surgery cannot be assessed from this trial design. Of the 20 patients with recurrent disease, 14 died as a result of distant metastases, which suggests that better systemic therapy is needed. The combination of docetaxel, cisplatin, and fluorouracil (TPF) in IC regimens has demonstrated improved response and OS rates with less toxicity.46-48
It is interesting to speculate whether nonresponders to IC with platinum and fluorouracil, HPV-negative patients, or patients with other unfavorable tumor biomarker profiles would benefit from the addition of a taxane up front.
The factors that govern the response to IC and the subsequent response to CRT are poorly understood. However, it is clear that HPV-positive tumors were most likely to respond to IC, whereas HPV-negative tumors were less likely to respond to IC or had borderline responses. All HPV-negative patients were former or current smokers. For reasons that are not entirely clear, smoking decreases the advantage of having an HPV-positive tumor. Kumar et al.24
examine the role of tumor biomarkers (ie, p53, BCLXL, and EGFR), patient characteristics, and HPV status in response to therapy and survival. They identify marker patterns associated with good response and survival and those associated with treatment failure and poor survival. These markers suggest potential targets for individualized treatment for patients who are unlikely to respond to CRT. It is clear that alternative treatment strategies must be developed for those patients least likely to benefit from IC and CRT or surgery and RT. Finally, the high incidence of high-risk HPV-associated cancers in men suggests that vaccination of all adolescents against this oncogenic risk should be considered.