Point/Counter

Can chemotherapy be omitted from treatment for HPV–associated head and neck cancer?

Click here to read the Cover Story, “Answers to ’critical questions’ may personalize treatment of HPV–associated head, neck cancer.”

POINT

Yes.

A growing subset of oropharyngeal squamous cell carcinomas are not initiated from smoking but from viral infection by HPV — mostly HPV16 — and they have superior locoregional control and survival rates after standard chemoradiation compared with other head and neck cancers. The original chemoradiation trials in oropharyngeal cancer (OPC) or unselected head and neck cancers showed significant survival advantages from the addition of concurrent platinum-based chemotherapy to radiation, but these trials did not stratify by or specifically analyze the HPV–positive OPC population.

Sue S. Yom, MD, PhD, MAS
Sue S. Yom

On the other hand, trials testing intensification of induction (DeCIDE, Paradigm, and Spanish Head and Neck Cancer Cooperative Group trials) or concurrent (RTOG 0522) chemotherapy have not succeeded, perhaps because so-called “low risk” patients with HPV–positive OPC — who comprised the majority of enrollment — do not seem to need intensification over standard treatment. Further, several large well-controlled institutional experiences and population-based analyses failed to demonstrate benefits from the indiscriminate addition of concurrent chemotherapy for all American Joint Committee on Cancer stage III to stage IV OPC, especially those with small-volume disease.

Additional support for single-modality radiation comes from an older feasibility trial of intensity-modulated radiation therapy for OPC with eligibility up to stage T2N1 (RTOG 0022); in this trial, locoregional disease control rates were 91% with all locoregional and distant failures in smokers. Meanwhile, on the surgery side, several single-institution reports of results with upfront transoral resection and neck dissection have reported successful outcomes with postoperative therapy consisting of radiation alone.

Surgical trials are testing whether chemotherapy may be omitted from postoperative management of HPV–positive OPC, even among those with extranodal extension. These trials include PATHOS NCT02215265 and ADEPT NCT01687413. Radiation-based HPV–positive OPC trials are examining regimens such as weekly cisplatin, concurrent cetuximab (Erbitux, Eli Lilly) and omission of chemotherapy (NRG-HN002 NCT02254278).

The question that will be settled over the next decade is no longer whether chemotherapy can be omitted in HPV–positive OPC, but which subgroups of patients still clearly merit chemotherapy. These scenarios might include patients with T4 or N2c-3 disease or extensive smoking history; those with risk factors not fully characterized in this population, such as supraclavicular nodes or extranodal extension; or those taking experimental radiation-reduction regimens based on induction chemotherapy.

The widening availability of targeted therapies or immunotherapies that are starting to be combined with radiation will create increasing impetus to supplant traditional chemotherapy in the HPV–positive OPC population, for whom long-term toxicities are a driving concern.

References:

Adelstein DJ, et al. J Clin Oncol. 2003;doi:10.1200/JCO.2003.01.008.

An Y, et al. Cancer. 2017;doi:10.1002/cncr.30598.

Ang KK, et al. J Clin Oncol. 2014;doi:10.1200/JCO.2013.53.5633.

Blanchard P, et al. Radiother Oncol. 2011;doi:10.1016/j.radonc.2011.05.036.

Chera BS, et al. Int J Radiat Oncol Biol Phys. 2015;doi:10.1016/j.ijrobp.2015.08.033.

Cohen EE, et al. J Clin Oncol. 2014;doi:10.1200/JCO.2013.54.6309.

Denis F, et al. J Clin Oncol. 2004;doi:10.1200/JCO.2004.08.021.

Garden AS, et al. Cancer. 2004;doi:10.1002/cncr.20069.

Haddad R, et al. Lancet Oncol. 2013;doi:10.1016/S1470-2045(13)70011-1.

Hall SF, et al. Head Neck. 2015;doi:10.1002/hed.23777.

Hitt R, et al. Ann Oncol. 2014;doi:10.1093/annonc/mdt461.

Sue S. Yom, MD, PhD, MAS, is associate professor in the departments of radiation oncology and otolaryngology — head and neck surgery at University of California, San Francisco. She can be reached at sue.yom@ucsf.edu. Disclosure: Yom reports research grant funding from Bristol-Myers Squibb, Genentech and Merck; a consultant role with BioMimetix; and royalties from Springer and UpToDate.

COUNTER

Chemoradiation remains standard treatment.

Improved prognosis for HPV–related oropharynx cancer has been demonstrated for patients managed with sequential multimodality therapy, chemoradiation or transoral resection with risk-based postoperative therapy. However, distant disease, including with later presentation, remains a source of treatment failure in HPV–related oropharynx cancer (OPC). Longer survival for patients with recurrent/metastatic HPV–associated disease, clinical observations in patients who refuse therapy, and a small percentage of cases with late distant disease indicate a different natural history for HPV–associated cancers, while high response rates to induction chemotherapy and chemoradiation imply greater treatment responsiveness.

Barbara A. Burtness, MD
Barbara A. Burtness

The highest cure rates (2-year survivals of 92%-96%) are observed among patients with nonbulky disease and a lifetime smoking exposure of 10 pack years or fewer, who are responsive to induction chemotherapy. The possibility of curing these favorable-risk patients while minimizing acute or long-term toxicity is appealing and has led to clinical trials testing strategies that variably omit chemotherapy, reduce radiation dose, or use minimally invasive surgery to bring disease burden to subclinical levels and incorporate pathologic findings into selection of risk-based adjuvant therapy. It is likely that each of these approaches will be appropriate for a subset of patients.

Level-one evidence comparing these approaches with each other or to standard chemoradiation has not been available, although a completed but not-yet-reported phase 3 trial (R1016) compared standard full-dose radiation plus high-dose cisplatin, with full-dose radiation plus weekly cetuximab (Erbitux, Eli Lilly). Absent a clinical trial, concurrent chemoradiation remains standard treatment. Investment in clinical trials exploring all of these paradigms is justified. However, because data show full radiation dose causes the greatest impact on long-term symptoms and functional impairment, and distant metastasis remains the greatest obstacle to cure, chemotherapy will be proven to be a critical component of curative therapy.

A number of endpoints will be key to evaluating each of these approaches. First, will radiation alone cure as many patients as chemoradiation or radiation with concurrent cetuximab? Likely not. Post-hoc analysis of a trial by Bonner and colleagues showed 3-year locoregional control for p16-expressing OPC was 65.4% with radiation alone compared with 87% for those treated with concurrent radiation and cetuximab. Although this study did not exclude patients with bulky disease, only 12% of those treated with radiation alone had T4 disease, indicating that many who recurred after radiation alone had T1-3 primary tumors. It will be important to determine to what extent omitting chemotherapy reduces oto- and nephrotoxicity, acute infield effects and late noncancer mortality and how the lifetime burden of these toxicities compares with the long-term effects of radiation on salivary gland and thyroid function, infield vascular disease, posttreatment cardiopulmonary decline, and the well-documented effects of pharyngeal constrictor doses above 54 Gy on long-term swallowing recovery. Given that trials dominated by patients with the more treatment-resistant HPV–negative cancers established radiation dosing strategies, is there benefit to administering full-dose radiation in favorable prognosis HPV–associated OPC? Lastly, what is the risk for distant metastatic disease in these patients, and when does this mandate inclusion of chemotherapy?

These questions will only be answered through well-designed clinical trials. Because of the low event rates in favorable-risk HPV–associated cancer, these will need to be large trials. Even large retrospective database analyses are plagued by low power. Reviewing the data available from small developmental trials, as well as from retrospective reviews, establishes some relevant points.

Two trials of induction chemotherapy followed by reduced radiation dose of chemotherapy-responsive patients have demonstrated that reducing radiation dose can reduce chronic toxicity. E1308 utilized three cycles of cisplatin/docetaxel/cetuximab induction chemotherapy followed for clinical complete responders by 54 Gy radiation with concurrent cetuximab. Results showed significant differences in 1-year swallowing and nutritional effects. Chen and colleagues employed carboplatin and paclitaxel induction, and treated patients with clinical response with 54 Gy radiation and weekly paclitaxel. Results showed lower rates of dysphagia and gastrostomy tube dependence than historical series using 70 Gy radiation.

An influential paper from Princess Margaret Hospital identified clinical characteristics associated with higher (24%) and lower (7%) risk for distant metastases. Within these groups, outcomes for radiation alone or chemoradiation were examined, and the paper purported to demonstrate that patients at low risk could safely be treated with radiation alone. However, as an example of the limited power of the analysis, a 10% difference in distant failure rate for patients with T2 disease (15% for radiation alone; 5% for chemoradiation) was not statistically significant given low patient numbers. Likewise, a retrospective analysis of 404 HPV–associated cancers from Princess Margaret Hospital and Istituto Nazionale dei Tumori failed to demonstrate a significant advantage in OS for patients who received more than 200 mg/m2 of concurrent cisplatin, despite a HR of 0.6 and small numerical differences in favor of higher-dose cisplatin for disease control, OS and locoregional control.

Thus, although these limitations in existing datasets make it easy to state that the decision to reduce chemotherapy dosing or treat patients with locally advanced HPV–related disease with radiation alone must await appropriately powered randomized clinical trials, I anticipate that — if appropriately powered — such trials will demonstrate systemic therapy is integral to curative therapy.

References:

Ang KK, et al. N Engl J Med. 2010;doi:10.1056/NEJMoa0912217.

Argiris A, et al. Ann Oncol. 2014;doi:10.1093/annonc/mdu167.

Bonner JA, et al. Lancet Oncol. 2010;doi:10.1016/S1470-2045(09)70311-0.

Chen AM, et al. Lancet Oncol. 2017;doi:10.1016/S1470-2045(17)30246-2.

Cohen MA, et al. Head Neck. 2011;doi:10.1002/hed.21500.

Fakhry C, et al. J Clin Oncol. 2014;doi:10.1200/JCO.2014.55.1937.

Fakhry C, et al. J Natl Cancer Inst. 2008;doi:10.1093/jnci/djn011.

Huang SH, et al. Oral Oncol. 2013;doi:10.1016/j.oraloncology.2012.07.015.

Marur S, et al. J Clin Oncol. 2016;doi:10.1200/JCO.2016.68.3300.

O’Sullivan B, et al. J Clin Oncol. 2013;doi:10.1200/JCO.2012.44.0164.

Posner MR, et al. Ann Oncol. 2011;doi:10.1093/annonc/mdr006.

Rosenthal DI, et al. J Clin Oncol. 2016;doi:10.1200/JCO.2015.62.5970.

Spreafico A, et al. Eur J Cancer. 2016;67:174-182.

Barbara A. Burtness, MD, is professor of medicine and leader of the head and neck cancer program at Yale Cancer Center, as well as a HemOnc Today Editorial Board member. She can be reached at barbara.burtness@yale.edu. Disclosure: Burtness reports no relevant financial disclosures.

Click here to read the Cover Story, “Answers to ’critical questions’ may personalize treatment of HPV–associated head, neck cancer.”

POINT

Yes.

A growing subset of oropharyngeal squamous cell carcinomas are not initiated from smoking but from viral infection by HPV — mostly HPV16 — and they have superior locoregional control and survival rates after standard chemoradiation compared with other head and neck cancers. The original chemoradiation trials in oropharyngeal cancer (OPC) or unselected head and neck cancers showed significant survival advantages from the addition of concurrent platinum-based chemotherapy to radiation, but these trials did not stratify by or specifically analyze the HPV–positive OPC population.

Sue S. Yom, MD, PhD, MAS
Sue S. Yom

On the other hand, trials testing intensification of induction (DeCIDE, Paradigm, and Spanish Head and Neck Cancer Cooperative Group trials) or concurrent (RTOG 0522) chemotherapy have not succeeded, perhaps because so-called “low risk” patients with HPV–positive OPC — who comprised the majority of enrollment — do not seem to need intensification over standard treatment. Further, several large well-controlled institutional experiences and population-based analyses failed to demonstrate benefits from the indiscriminate addition of concurrent chemotherapy for all American Joint Committee on Cancer stage III to stage IV OPC, especially those with small-volume disease.

Additional support for single-modality radiation comes from an older feasibility trial of intensity-modulated radiation therapy for OPC with eligibility up to stage T2N1 (RTOG 0022); in this trial, locoregional disease control rates were 91% with all locoregional and distant failures in smokers. Meanwhile, on the surgery side, several single-institution reports of results with upfront transoral resection and neck dissection have reported successful outcomes with postoperative therapy consisting of radiation alone.

Surgical trials are testing whether chemotherapy may be omitted from postoperative management of HPV–positive OPC, even among those with extranodal extension. These trials include PATHOS NCT02215265 and ADEPT NCT01687413. Radiation-based HPV–positive OPC trials are examining regimens such as weekly cisplatin, concurrent cetuximab (Erbitux, Eli Lilly) and omission of chemotherapy (NRG-HN002 NCT02254278).

The question that will be settled over the next decade is no longer whether chemotherapy can be omitted in HPV–positive OPC, but which subgroups of patients still clearly merit chemotherapy. These scenarios might include patients with T4 or N2c-3 disease or extensive smoking history; those with risk factors not fully characterized in this population, such as supraclavicular nodes or extranodal extension; or those taking experimental radiation-reduction regimens based on induction chemotherapy.

The widening availability of targeted therapies or immunotherapies that are starting to be combined with radiation will create increasing impetus to supplant traditional chemotherapy in the HPV–positive OPC population, for whom long-term toxicities are a driving concern.

References:

Adelstein DJ, et al. J Clin Oncol. 2003;doi:10.1200/JCO.2003.01.008.

An Y, et al. Cancer. 2017;doi:10.1002/cncr.30598.

Ang KK, et al. J Clin Oncol. 2014;doi:10.1200/JCO.2013.53.5633.

Blanchard P, et al. Radiother Oncol. 2011;doi:10.1016/j.radonc.2011.05.036.

Chera BS, et al. Int J Radiat Oncol Biol Phys. 2015;doi:10.1016/j.ijrobp.2015.08.033.

Cohen EE, et al. J Clin Oncol. 2014;doi:10.1200/JCO.2013.54.6309.

Denis F, et al. J Clin Oncol. 2004;doi:10.1200/JCO.2004.08.021.

Garden AS, et al. Cancer. 2004;doi:10.1002/cncr.20069.

Haddad R, et al. Lancet Oncol. 2013;doi:10.1016/S1470-2045(13)70011-1.

Hall SF, et al. Head Neck. 2015;doi:10.1002/hed.23777.

Hitt R, et al. Ann Oncol. 2014;doi:10.1093/annonc/mdt461.

Sue S. Yom, MD, PhD, MAS, is associate professor in the departments of radiation oncology and otolaryngology — head and neck surgery at University of California, San Francisco. She can be reached at sue.yom@ucsf.edu. Disclosure: Yom reports research grant funding from Bristol-Myers Squibb, Genentech and Merck; a consultant role with BioMimetix; and royalties from Springer and UpToDate.

PAGE BREAK

COUNTER

Chemoradiation remains standard treatment.

Improved prognosis for HPV–related oropharynx cancer has been demonstrated for patients managed with sequential multimodality therapy, chemoradiation or transoral resection with risk-based postoperative therapy. However, distant disease, including with later presentation, remains a source of treatment failure in HPV–related oropharynx cancer (OPC). Longer survival for patients with recurrent/metastatic HPV–associated disease, clinical observations in patients who refuse therapy, and a small percentage of cases with late distant disease indicate a different natural history for HPV–associated cancers, while high response rates to induction chemotherapy and chemoradiation imply greater treatment responsiveness.

Barbara A. Burtness, MD
Barbara A. Burtness

The highest cure rates (2-year survivals of 92%-96%) are observed among patients with nonbulky disease and a lifetime smoking exposure of 10 pack years or fewer, who are responsive to induction chemotherapy. The possibility of curing these favorable-risk patients while minimizing acute or long-term toxicity is appealing and has led to clinical trials testing strategies that variably omit chemotherapy, reduce radiation dose, or use minimally invasive surgery to bring disease burden to subclinical levels and incorporate pathologic findings into selection of risk-based adjuvant therapy. It is likely that each of these approaches will be appropriate for a subset of patients.

Level-one evidence comparing these approaches with each other or to standard chemoradiation has not been available, although a completed but not-yet-reported phase 3 trial (R1016) compared standard full-dose radiation plus high-dose cisplatin, with full-dose radiation plus weekly cetuximab (Erbitux, Eli Lilly). Absent a clinical trial, concurrent chemoradiation remains standard treatment. Investment in clinical trials exploring all of these paradigms is justified. However, because data show full radiation dose causes the greatest impact on long-term symptoms and functional impairment, and distant metastasis remains the greatest obstacle to cure, chemotherapy will be proven to be a critical component of curative therapy.

PAGE BREAK

A number of endpoints will be key to evaluating each of these approaches. First, will radiation alone cure as many patients as chemoradiation or radiation with concurrent cetuximab? Likely not. Post-hoc analysis of a trial by Bonner and colleagues showed 3-year locoregional control for p16-expressing OPC was 65.4% with radiation alone compared with 87% for those treated with concurrent radiation and cetuximab. Although this study did not exclude patients with bulky disease, only 12% of those treated with radiation alone had T4 disease, indicating that many who recurred after radiation alone had T1-3 primary tumors. It will be important to determine to what extent omitting chemotherapy reduces oto- and nephrotoxicity, acute infield effects and late noncancer mortality and how the lifetime burden of these toxicities compares with the long-term effects of radiation on salivary gland and thyroid function, infield vascular disease, posttreatment cardiopulmonary decline, and the well-documented effects of pharyngeal constrictor doses above 54 Gy on long-term swallowing recovery. Given that trials dominated by patients with the more treatment-resistant HPV–negative cancers established radiation dosing strategies, is there benefit to administering full-dose radiation in favorable prognosis HPV–associated OPC? Lastly, what is the risk for distant metastatic disease in these patients, and when does this mandate inclusion of chemotherapy?

These questions will only be answered through well-designed clinical trials. Because of the low event rates in favorable-risk HPV–associated cancer, these will need to be large trials. Even large retrospective database analyses are plagued by low power. Reviewing the data available from small developmental trials, as well as from retrospective reviews, establishes some relevant points.

Two trials of induction chemotherapy followed by reduced radiation dose of chemotherapy-responsive patients have demonstrated that reducing radiation dose can reduce chronic toxicity. E1308 utilized three cycles of cisplatin/docetaxel/cetuximab induction chemotherapy followed for clinical complete responders by 54 Gy radiation with concurrent cetuximab. Results showed significant differences in 1-year swallowing and nutritional effects. Chen and colleagues employed carboplatin and paclitaxel induction, and treated patients with clinical response with 54 Gy radiation and weekly paclitaxel. Results showed lower rates of dysphagia and gastrostomy tube dependence than historical series using 70 Gy radiation.

An influential paper from Princess Margaret Hospital identified clinical characteristics associated with higher (24%) and lower (7%) risk for distant metastases. Within these groups, outcomes for radiation alone or chemoradiation were examined, and the paper purported to demonstrate that patients at low risk could safely be treated with radiation alone. However, as an example of the limited power of the analysis, a 10% difference in distant failure rate for patients with T2 disease (15% for radiation alone; 5% for chemoradiation) was not statistically significant given low patient numbers. Likewise, a retrospective analysis of 404 HPV–associated cancers from Princess Margaret Hospital and Istituto Nazionale dei Tumori failed to demonstrate a significant advantage in OS for patients who received more than 200 mg/m2 of concurrent cisplatin, despite a HR of 0.6 and small numerical differences in favor of higher-dose cisplatin for disease control, OS and locoregional control.

PAGE BREAK

Thus, although these limitations in existing datasets make it easy to state that the decision to reduce chemotherapy dosing or treat patients with locally advanced HPV–related disease with radiation alone must await appropriately powered randomized clinical trials, I anticipate that — if appropriately powered — such trials will demonstrate systemic therapy is integral to curative therapy.

References:

Ang KK, et al. N Engl J Med. 2010;doi:10.1056/NEJMoa0912217.

Argiris A, et al. Ann Oncol. 2014;doi:10.1093/annonc/mdu167.

Bonner JA, et al. Lancet Oncol. 2010;doi:10.1016/S1470-2045(09)70311-0.

Chen AM, et al. Lancet Oncol. 2017;doi:10.1016/S1470-2045(17)30246-2.

Cohen MA, et al. Head Neck. 2011;doi:10.1002/hed.21500.

Fakhry C, et al. J Clin Oncol. 2014;doi:10.1200/JCO.2014.55.1937.

Fakhry C, et al. J Natl Cancer Inst. 2008;doi:10.1093/jnci/djn011.

Huang SH, et al. Oral Oncol. 2013;doi:10.1016/j.oraloncology.2012.07.015.

Marur S, et al. J Clin Oncol. 2016;doi:10.1200/JCO.2016.68.3300.

O’Sullivan B, et al. J Clin Oncol. 2013;doi:10.1200/JCO.2012.44.0164.

Posner MR, et al. Ann Oncol. 2011;doi:10.1093/annonc/mdr006.

Rosenthal DI, et al. J Clin Oncol. 2016;doi:10.1200/JCO.2015.62.5970.

Spreafico A, et al. Eur J Cancer. 2016;67:174-182.

Barbara A. Burtness, MD, is professor of medicine and leader of the head and neck cancer program at Yale Cancer Center, as well as a HemOnc Today Editorial Board member. She can be reached at barbara.burtness@yale.edu. Disclosure: Burtness reports no relevant financial disclosures.