Organ Preservation for Advanced Resectable Cancer of the Base of Tongue and Hypopharynx: A Southwest Oncology Group Trial
http://www.100md.com
《临床肿瘤学》
the University of Michigan Medical Center, Ann Arbor
Wayne State University Medical Center, Detroit, MI
Southwest Oncology Group Statistical Center, Seattle, WA
Eastern Virginia Medical School, Norfolk, VA
Cleveland Clinic Foundation, Cleveland
Ohio State University Medical Center, Columbus, OH
University of Arkansas for Medical Science, Little Rock, AR
ABSTRACT
PATIENTS AND METHODS: Fifty-nine eligible patients were enrolled; 37 had base of tongue cancer, and 22 had hypopharynx cancer. Forty-two percent had stage III disease, and 58% had stage IV disease. Induction chemotherapy was two cycles of cisplatin 100 mg/m2 and fluorouracil 1,000 mg/m2/d for 5 days. Patients who had a greater than 50% response at the primary site were treated with radiation 72Gy and concurrent cisplatin 100 mg/m2 for three cycles. Patients with less than partial response at the primary had immediate salvage surgery.
RESULTS: Forty-five patients (76%) had a greater than 50% response at the primary after induction chemotherapy; 43 went on to receive definitive chemoradiotherapy. Thirty-two patients (54%) achieved a histologic complete response at the primary site, and an additional nine patients had a complete clinical response, but biopsy was not done. Seventy-five percent of patients did not require surgery at the primary tumor site. The 3-year overall survival was 64%. The 3-year progression-free survival with organ preservation was 52%.
CONCLUSION: Patients with base of tongue or hypopharyngeal cancer treated with this regimen of induction chemotherapy followed by definitive chemoradiotherapy have a good rate of organ preservation without compromise of survival.
INTRODUCTION
The treatment regimen included two cycles of induction chemotherapy followed by chemoradiotherapy for responders. The rationale for induction chemotherapy, as identified by the Veterans Administration Larynx Trial,1 was to select the patients most likely to have tumors sensitive to chemoradiotherapy. Chemoradiotherapy is a treatment approach which has demonstrated superiority compared with radiation alone as definitive therapy.2-4 Our main objective was to evaluate the histologic complete response rate at the primary tumor site after treatment with induction chemotherapy followed by concomitant chemoradiotherapy.
PATIENTS AND METHODS
Eligibility criteria included the following: newly diagnosed, previously untreated squamous cell carcinoma of the base of the tongue or hypopharynx; selected stage III (T2N1M0, T3N0M0, T3N1M0) or IV (T2N2M0, T3N2M0, T2N3M0, T3N3M0) disease without distant metastases (T4 tumors were excluded because they are frequently considered unresectable for cure); surgically resectable disease (for patients with hypopharyngeal cancer, the surgery, which was required for the tumor, had be total laryngectomy); measurable disease documented by a computed tomography (CT) or magnetic resonance imaging (MRI) scan; and a Southwest Oncology Group performance status of 0 or 1. Average hearing loss in both ears could not exceed 40 dB in the 50 to 2,000 Hz range. Patients had adequate laboratory parameters, were informed of the investigational nature of this study, and gave written informed consent. The study was approved by local institutional review boards and conducted at seven institutions under the auspices of the Southwest Oncology Group.
Second registration (before concomitant chemotherapy and radiation). Patients had to complete induction chemotherapy and undergo assessment by clinical exam, CT, or MRI ± endoscopy on approximately day 43. At this assessment, patients had to have ≥ 50% tumor reduction at the primary site with no evidence of progressive disease elsewhere.
Treatment Plan
Induction chemotherapy. Cisplatin 100 mg/m2 was infused over 90 minutes, and fluorouracil 1,000 mg/m2/d was given as a 24-hour infusion for 5 days, every 21 days, for two cycles. An aggressive regimen of hydration and antiemetics was recommended.
Tumor assessment. After two full cycles of chemotherapy, tumor assessment was done on approximately day 43. This consisted of a clinical examination by Otolaryngology/Head and Neck Surgery, CT scan, or MRI, and endoscopy if warranted. If progressive disease was documented, or if there was less than 50% tumor reduction at the primary site, the patient had immediate surgical resection. Patients who had ≥ 50% tumor reduction at the primary site were re-registered and referred for definitive chemoradiotherapy.
For measurable disease (measurable in two dimensions), a partial response at the end of induction was defined as a decrease of ≥ 50% under the baseline in the product of the perpendicular diameters of a lesion. For assessable disease (not measurable in two dimensions), a partial response at the end of induction was defined as a decrease of ≥ 50%, in the opinion of the treating physician.
Concomitant chemoradiotherapy. The regimen was started within 21 to 28 days, measured from the first day of cycle 2 of induction chemotherapy. Cisplatin 100 mg/m2 was infused over 90 minutes every 21 days for three cycles, concurrent with the radiation therapy.
The prechemotherapy volume of tumor was treated with radiation. The initial field was the total volume, which included the primary tumor, any enlarged lymph nodes, and all areas at risk for microscopic disease. After treating the total volume, a boost volume was treated. The boost volume included the primary with a 2-cm margin, along with enlarged lymph nodes. In hypopharyngeal primaries, the lower level of the boost volume was below the cricoid. In the case where there were clinically enlarged lymph nodes, the initial total volume included all the levels of neck nodes, including the retropharyngeal nodes at the base of the skull. In the case of a clinically negative neck both by clinical and CT examination, the fields included the upper, middle, and lower cervical nodes (levels 2, 3, 4) in the total volume. Radiation therapy began on day 1 of concomitant chemotherapy. Radiation therapy was given once a day at 1.8 Gy per fraction to a total dose of 50.4 Gy in 28 fractions to the total volume. The boost volume was then treated at 1.80 Gy per fraction once a day to 19.8 Gy in 11 fractions. Thus, the total dose to the tumor was 70.2 Gy and areas at risk for microscopic disease received 50.4 Gy.
The spinal cord was blocked from the upper neck fields at a dose of 39.6 Gy and the blocked posterior neck was boosted to bring the dose of the blocked posterior neck field to 50 Gy. The dose to the tumor at midline, neck nodes at 1.5 cm in the midneck at the level of the thyroid cartilage, and spinal cord dose along with the central axis and supraclavicular dose at 3 cm were recorded in all cases. The minimum dose to the primary was 70.2 Gy. The dose to enlarged lymph nodes < 2 cm was 66 Gy, and > 2 cm was 70 Gy. The dose for all areas at risk for microscopic disease was 50.4 Gy. Spinal cord dose was not to exceed 45 Gy.
The spinal cord was to be shielded by a midline block in the lower neck field or a corner block in the upper neck field.
Final tumor assessment. Patients treated on the concomitant radiation/chemotherapy regimen underwent final evaluation 8 to 12 weeks after the completion of radiation. This evaluation consisted of a clinical exam by the otolaryngologist/head and neck surgeon, CT scan, or MRI to document tumor response and endoscopy. Biopsies were taken from the primary site, previously involved lymph nodes, and any other suspicious areas.
Patients who achieved clinical and pathologic complete response at the primary site had no further treatment and entered a program of close observation. Patients who had residual neoplasm verified pathologically with biopsy at the primary site had surgical resection. The resection was the original surgical resection that would have been performed at the time of initial diagnosis.
The decision regarding node dissection was made independently of the decision regarding the primary site. Patients with any clinical evidence of residual nodal involvement had an appropriate neck dissection. Patients with no evidence of clinical or pathologic disease in the regional lymph nodes did not undergo neck dissection.
Statistical Considerations
The primary outcome of interest was the histologic complete response rate for each primary tumor site, with no progression of involved nodes, after completion of induction chemotherapy followed by chemoradiotherapy. This would be interpreted as the rate of organ preservation. The study design specified that a confirmed complete histologic response rate at the primary site ≥ 50% would be of interest; further testing would not be pursued if the complete histologic response rate at the primary site was ≤ 25%. At the time of initial registration, patients were stratified by tumor site: hypopharynx versus base of tongue. Initially, 20 patients from each tumor site were accrued. If at least five complete responses at the primary site were observed, 15 additional patients would be accrued. Fourteen or more complete responses (out of 35) at the primary site would be considered as evidence warranting further study of this regimen for organ preservation, provided other factors, such as toxicity and survival, also appeared favorable. This design had a significance level (probability of falsely declaring a 20% complete response probability to warrant further study) of 4% and a power of 91%.
Assuming complete follow-up, 35 patients were sufficient to estimate the 3-year overall survival probability and 3-year progression-free survival probability to within ± 0.17 (95% CI).
As a secondary end point, organ preservation was evaluated by observing the number of patients who underwent salvage surgery at the primary site. The end point of 3-year progression-free survival with organ preservation was estimated. Using this end point, a patient was considered as a "failure" at the earliest documented time of death, progression of disease, or salvage surgery at the primary site. Assuming complete follow-up, 35 patients are sufficient to estimate the 3-year progression-free survival with organ preservation to within ± 0.17 (95% CI).
The 3-year overall survival, progression-free survival, and progression-free survival with organ preservation probabilities were estimated using the method of Kaplan and Meier.5
RESULTS
Toxicity
Treatment was tolerated well. Grade 4 toxicities (mostly hematologic) occurred in 17 of 59 patients (29%) during induction chemotherapy, and in 8 of 42 patients (19%) during concurrent chemoradiotherapy. The most common toxicities are listed in Table 2. One patient refused any concurrent chemoradiotherapy and was not assessable for toxicity during concurrent therapy. There was one death attributed to treatment, which occurred during induction chemotherapy, resulting from renal failure and sepsis.
Quality-of-life measurements, such as swallowing function, percentage of patients requiring a feeding tube or tracheostomy during long-term follow-up, and the incidence of radionecrosis, are important parameters of organ preservation to report. However, this study was not designed or funded to collect this data or to track patients for toxicities over a long period of time. Therefore this information is not available.
Induction Chemotherapy: Clinical Response at the Primary Tumor Site
Fifty-nine eligible patients were treated with induction chemotherapy (Table 3). After completion of this induction chemotherapy, patients were evaluated for local response, which was defined ≥ 50% reduction in the primary tumor. Forty-seven patients (80%) received two cycles of induction chemotherapy, and 12 patients (20%) received less than two full cycles. Forty-six patients (78%) had a > 50% response at the primary site. Forty-three of these patients went on to receive concurrent chemoradiotherapy. Three responders did not receive concurrent chemoradiotherapy: two as a result of toxicity from induction chemotherapy who subsequently received radiation alone, and the other refused any further protocol treatment.
Seven patients (12%) completed induction treatment but had < 50% response at the primary tumor site. Of those, five patients received salvage surgery, one refused surgery, and one developed incurable progressive disease.
Six patients (10%) did not complete induction chemotherapy and could not be evaluated for local response at the primary. This includes two patients who died before assessment (one due to disease, the other due to toxicity), and four who were removed from protocol treatment as a result of either toxicity (three patients) or patient noncompliance (one patient).
Chemoradiotherapy: Histologic Response at the Primary Tumor Site
The primary objective of this study was defined as the rate of complete histologic response at the primary tumor site after treatment with induction chemotherapy followed by concomitant chemoradiotherapy (Table 4). Out of 59 eligible patients enrolled, 16 patients did not receive chemoradiotherapy for reasons described in the previous section. Forty-three patients went on to receive chemoradiotherapy. Thirty-two patients (74%) received two to three cycles of chemotherapy concurrent with the radiation, five patients (12%) received less than two cycles of chemotherapy, and six patients (14%) received no chemotherapy. Thirty-two patients (54%) achieved a documented histologic complete response. There were nine additional patients who achieved a complete clinical response at the primary tumor site at time of endoscopy following the completion of chemoradiotherapy, but they did not undergo the recommended biopsies.
Two patients had residual disease after chemoradiotherapy: One had clinical residual disease at the primary site and had salvage surgery, and one patient developed metastatic disease. No biopsies were performed.
Salvage Surgery at the Primary Site at Completion of Protocol
We also looked at the results using a definition for the end point of organ preservation that included as a "success" any patient for whom salvage surgery of the primary was not necessary immediately following completion of the treatment regimen, because of excellent response to the therapy (Table 5). Using these criteria, 44 patients (75%) were classified as organ preservation success; 41 patients who required no surgery at the primary site or neck, and three patients who required a neck dissection only. The 44 patients who did not require salvage surgery included 32 patients who had histologic verification of a complete response at the primary site, nine patients who had a clinical complete response at the primary site, and the three patients who had > 50% clinical response at the primary site after induction chemotherapy, but did not receive concurrent chemoradiotherapy. One of these patients could not get more chemotherapy because of neutropenia, was treated off protocol with definitive radiation alone, and was disease-free at last contact. The second patient discontinued protocol treatment because of abdominal discomfort, was treated off protocol with radiation and cisplatin, and was disease-free at last contact. The third patient refused chemoradiotherapy after a complete response to the induction regimen, was treated off protocol with radiation alone, and was disease-free at last contact. None of those patients required salvage surgery at the date of last contact.
Nine patients did not have salvage surgery, but should not be considered successes because they either refused surgery (one patient), did not complete induction chemotherapy due to toxicity (three patients) or noncompliance (one patient) and thus were never assessed for local response, or had developed locally unresectable disease (one patient), metastases (one patient), or had died (two patients).
Six patients had salvage surgery at the time of planned assessment immediately following the end of treatment, five "early" (immediately following induction chemotherapy) and one "late" (immediately following concurrent chemoradiotherapy). Of the five patients who had early planned salvage surgery, two eventually developed local recurrence of disease and died, one developed a neck recurrence and died, and two remained free of disease. The patient who had late planned salvage surgery was alive and disease-free at date of last contact. In addition, one of the complete responders eventually received salvage surgery because of progression of disease at the primary site 8 months later, and died of cancer 16 months afterwards.
Overall, surgical salvage was performed in five (38%) of 13 patients who had < 50% response to induction chemotherapy, in one (50%) of two patients who had persistent disease after completion of chemoradiotherapy, and in the one patient who eventually had a local recurrence.
The data included in Tables 3, 4, and 5 are summarized in a flow chart in Figure 1.
Survival
All eligible patients were included in the analysis for survival, progression-free survival, and progression-free survival with organ preservation. Median follow-up for patients still alive is 51 months (50 months for base of tongue cancer patients, and 52 months for hypopharynx cancer patients).
The 3-year overall survival estimate is 64% for all patients (95% CI, 0.52 to 0.76), 67% for base of tongue (95% CI, 0.52 to 0.83), and 58% for hypopharynx (95% CI, 0.37 to 0.79; Fig 2)
The 3-year progression-free survival estimate is 57% for all patients (95% CI, 0.44 to 0.70), 62% for base of tongue (95% CI, 0.47 to 0.78), and 48% for hypopharynx (95% CI, 0.27 to 0.70; Fig 3).
The 3-year progression-free survival with organ preservation estimate is 52% for all patients (95% CI, 0.39 to 0.65), 62% for base of tongue (95% CI, 0.47 to 0.78), and 34% for hypopharynx (95% CI, 0.14 to 0.55; Fig 4).
Eighteen (39%) of the patients who had > 50% response at the primary after induction chemotherapy have eventually relapsed or died.
DISCUSSION
Our primary end point, the achievement of a histologic complete response at the primary site following chemoradiotherapy, was achieved by 54% of the patients enrolled. Additionally, another 15% of patients achieved a complete clinical response at the primary tumor site, although a biopsy confirmation was not obtained. The 64% overall survival at 3 years for the selected stage III and IV patients in our trial compares favorably to other reported data.
Surgery remains a critical treatment modality in organ preservation approaches for nonresponders and for those who experienced late locoregional failures. The 3-year survival of patients who underwent surgery in this protocol was 43% (three of seven patients), which is similar to data in a recently reported meta-analysis for salvage surgery in 1,080 patients (5-year survival = 39%).10 In the Veterans Affairs larynx1 and European Organisation for Research and Treatment of Cancer hypopharynx11 trials, the rates of surgery were 36% and 42%, respectively. However, surgical rates can be as low as 16% when cisplatin-based chemoradiotherapy is used in the larynx.12 In this protocol, 12% (seven of 59 patients) underwent surgery. Since some patients refused surgery, it is imperative that patients who are treated in an organ preservation approach are made aware that salvage surgery remains a possible therapeutic option. In this study, 58% (34 of 59 patients) had N2- or N3-stage disease. Although neck dissection in this protocol was done only for those patients with clinical residual disease, a planned neck dissection may be considered for patients who present with N2 and N3 disease if primary disease is controlled, since this may improve regional control.13
Several trials for organ preservation have included patients with base of tongue and hypopharyngeal cancer.14-17 The University of Michigan reported two sequential trials of induction chemotherapy followed by definitive radiation for patients with advanced head and neck cancer.14 Twenty-six patients had base of tongue cancer, and 34 patients had hypopharyngeal cancer. Seventy-one percent had stage IV disease; 36% had T4 tumors. After treatment was completed, 58% of those with base of tongue cancer and 59% of those with hypopharyngeal cancer were spared surgery to the primary site. Overall survival for the whole group at 3 years was 42%.
The University of Pennsylvania Cancer Center Clinical Trials Group treated 53 patients with two cycles of carboplatin and paclitaxel induction chemotherapy.17 Patients with a major response were then treated with definitive chemoradiotherapy and paclitaxel. Thirty-three patients in this group had base of tongue cancer. Organ preservation was achieved in 77% of all patients, and 3-year survival was 70%, which is similar to our results.
We are encouraged that our results provide good data demonstrating that organ preservation is achievable in a substantial number of patients with base of tongue or hypopharyngeal cancer. When we designed this phase II trial, we had anticipated proceeding to a randomized trial comparing this regimen to surgery. However, over time there has been a general trend away from surgery for these patients, in favor of chemoradiotherapy. Many potential investigators felt reluctant to participate in a trial in which patients might be assigned to surgery, without the chance for organ preservation.
In summary, our data show that this organ preservation treatment approach is feasible and tolerable for this selected group of stage III and IV patients in a multi-institutional setting. The benefit of induction chemotherapy before chemoradiotherapy is not clearly defined, and deserves further testing in a randomized setting compared with chemoradiotherapy alone. The current direction of the Southwest Oncology Group is to investigate alternative combinations of chemotherapy and radiation, and to identify molecular markers that may help select patients for the most suitable treatment modality.
Authors’ Disclosures of Potential Conflicts of Interest
NOTES
Supported in part by the following Public Health Services Cooperative Agreement grants awarded by the National Cancer Institute’s Department of Health and Human Services: CA38926, CA32102, CA27057, CA14028, CA37981, CA58416, CA03096, CA58686, CA74647.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
1. Wolf GT, Hong WK, Fisher SG, et al: Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med 324:1685-1690, 1991
2. Brizel DM, Albers ME, Fisher SR, et al: Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 338:1798-1804, 1998
3. Calais G, Alfonsi M, Bardet E, et al: Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Natl Cancer Inst 91:2081-2086, 1999
4. Adelstein DJ, Lavertu P, Saxton JP, et al: Mature results of a phase III randomized trial comparing concurrent chemoradiotherapy with radiation therapy alone in patients with stage III and IV squamous cell carcinoma of the head and neck. Cancer 88:876-883, 2000
5. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958
6. Pignon J, Baujat B, Hill C, et al: Locally advanced head and neck cancer: Meta-analysis of updated individual data. Euro Ca Conf (ECCO-11) 37:S135, 2001
7. Denis F, Garaud P, Bardet E, et al: Final results of the 94-01 French head and neck oncology and radiotherapy group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. J Clin Oncol 22:69-76, 2004
8. De Andres L, Brunet J, Lopez-Pousa A, et al: Randomized trial of neoadjuvant cisplatin and fluorouracil versus carboplatin and fluorouracil in patients with stage IV-M0 head and neck cancer. J Clin Oncol 13:1493-1500, 1995
9. Forastiere AA, Metch B, Schuller DE, et al: Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: A Southwest Oncology Group study. J Clin Oncol 10:1245-1251, 1992
10. Goodwin WJ Jr: Salvage surgery for patients with recurrent squamous cell carcinoma of the upper aerodigestive tract: When do the ends justify the means Laryngoscope 110:1-18, 2000 (suppl 93)
11. Lefebvre JL, Chevalier D, Luboinski B, et al: Larynx preservation in pyriform sinus cancer: Preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst 88:890-899, 1996
12. Forastiere AA, Goepfert H, Maor M, et al: Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 349:2091-2098, 2003
13. Mendenhall WM, Villaret DB, Amdur RJ, et al: Planned neck dissection after definitive radiotherapy for squamous cell carcinoma of the head and neck. Head Neck 24:1012-1018, 2002
14. Urba SG, Wolf GT, Bradford CR, et al: Neoadjuvant therapy for organ preservation in head and neck cancer. Laryngoscope 110:2074-2080, 2000
15. Urba SG, Forastiere AA, Wolf GT, et al: Intensive induction chemotherapy and radiation for organ preservation in patients with advanced resectable head and neck carcinoma. J Clin Oncol 12:946-953, 1994
16. Pfister DG, Harrison LB, Strong EW, et al: Organ-function preservation in advanced oropharynx cancer: Results with induction chemotherapy and radiation. J Clin Oncol 13:671-680, 1995
17. Machtay M, Rosenthal DI, Hershock D, et al: Organ preservation therapy using induction plus concurrent chemoradiation for advanced respectable oropharyngeal carcinoma: A University of Pennsylvania phase II trial. J Clin Oncol 20:3964-3971, 2002(Susan G. Urba, James Moon)
Wayne State University Medical Center, Detroit, MI
Southwest Oncology Group Statistical Center, Seattle, WA
Eastern Virginia Medical School, Norfolk, VA
Cleveland Clinic Foundation, Cleveland
Ohio State University Medical Center, Columbus, OH
University of Arkansas for Medical Science, Little Rock, AR
ABSTRACT
PATIENTS AND METHODS: Fifty-nine eligible patients were enrolled; 37 had base of tongue cancer, and 22 had hypopharynx cancer. Forty-two percent had stage III disease, and 58% had stage IV disease. Induction chemotherapy was two cycles of cisplatin 100 mg/m2 and fluorouracil 1,000 mg/m2/d for 5 days. Patients who had a greater than 50% response at the primary site were treated with radiation 72Gy and concurrent cisplatin 100 mg/m2 for three cycles. Patients with less than partial response at the primary had immediate salvage surgery.
RESULTS: Forty-five patients (76%) had a greater than 50% response at the primary after induction chemotherapy; 43 went on to receive definitive chemoradiotherapy. Thirty-two patients (54%) achieved a histologic complete response at the primary site, and an additional nine patients had a complete clinical response, but biopsy was not done. Seventy-five percent of patients did not require surgery at the primary tumor site. The 3-year overall survival was 64%. The 3-year progression-free survival with organ preservation was 52%.
CONCLUSION: Patients with base of tongue or hypopharyngeal cancer treated with this regimen of induction chemotherapy followed by definitive chemoradiotherapy have a good rate of organ preservation without compromise of survival.
INTRODUCTION
The treatment regimen included two cycles of induction chemotherapy followed by chemoradiotherapy for responders. The rationale for induction chemotherapy, as identified by the Veterans Administration Larynx Trial,1 was to select the patients most likely to have tumors sensitive to chemoradiotherapy. Chemoradiotherapy is a treatment approach which has demonstrated superiority compared with radiation alone as definitive therapy.2-4 Our main objective was to evaluate the histologic complete response rate at the primary tumor site after treatment with induction chemotherapy followed by concomitant chemoradiotherapy.
PATIENTS AND METHODS
Eligibility criteria included the following: newly diagnosed, previously untreated squamous cell carcinoma of the base of the tongue or hypopharynx; selected stage III (T2N1M0, T3N0M0, T3N1M0) or IV (T2N2M0, T3N2M0, T2N3M0, T3N3M0) disease without distant metastases (T4 tumors were excluded because they are frequently considered unresectable for cure); surgically resectable disease (for patients with hypopharyngeal cancer, the surgery, which was required for the tumor, had be total laryngectomy); measurable disease documented by a computed tomography (CT) or magnetic resonance imaging (MRI) scan; and a Southwest Oncology Group performance status of 0 or 1. Average hearing loss in both ears could not exceed 40 dB in the 50 to 2,000 Hz range. Patients had adequate laboratory parameters, were informed of the investigational nature of this study, and gave written informed consent. The study was approved by local institutional review boards and conducted at seven institutions under the auspices of the Southwest Oncology Group.
Second registration (before concomitant chemotherapy and radiation). Patients had to complete induction chemotherapy and undergo assessment by clinical exam, CT, or MRI ± endoscopy on approximately day 43. At this assessment, patients had to have ≥ 50% tumor reduction at the primary site with no evidence of progressive disease elsewhere.
Treatment Plan
Induction chemotherapy. Cisplatin 100 mg/m2 was infused over 90 minutes, and fluorouracil 1,000 mg/m2/d was given as a 24-hour infusion for 5 days, every 21 days, for two cycles. An aggressive regimen of hydration and antiemetics was recommended.
Tumor assessment. After two full cycles of chemotherapy, tumor assessment was done on approximately day 43. This consisted of a clinical examination by Otolaryngology/Head and Neck Surgery, CT scan, or MRI, and endoscopy if warranted. If progressive disease was documented, or if there was less than 50% tumor reduction at the primary site, the patient had immediate surgical resection. Patients who had ≥ 50% tumor reduction at the primary site were re-registered and referred for definitive chemoradiotherapy.
For measurable disease (measurable in two dimensions), a partial response at the end of induction was defined as a decrease of ≥ 50% under the baseline in the product of the perpendicular diameters of a lesion. For assessable disease (not measurable in two dimensions), a partial response at the end of induction was defined as a decrease of ≥ 50%, in the opinion of the treating physician.
Concomitant chemoradiotherapy. The regimen was started within 21 to 28 days, measured from the first day of cycle 2 of induction chemotherapy. Cisplatin 100 mg/m2 was infused over 90 minutes every 21 days for three cycles, concurrent with the radiation therapy.
The prechemotherapy volume of tumor was treated with radiation. The initial field was the total volume, which included the primary tumor, any enlarged lymph nodes, and all areas at risk for microscopic disease. After treating the total volume, a boost volume was treated. The boost volume included the primary with a 2-cm margin, along with enlarged lymph nodes. In hypopharyngeal primaries, the lower level of the boost volume was below the cricoid. In the case where there were clinically enlarged lymph nodes, the initial total volume included all the levels of neck nodes, including the retropharyngeal nodes at the base of the skull. In the case of a clinically negative neck both by clinical and CT examination, the fields included the upper, middle, and lower cervical nodes (levels 2, 3, 4) in the total volume. Radiation therapy began on day 1 of concomitant chemotherapy. Radiation therapy was given once a day at 1.8 Gy per fraction to a total dose of 50.4 Gy in 28 fractions to the total volume. The boost volume was then treated at 1.80 Gy per fraction once a day to 19.8 Gy in 11 fractions. Thus, the total dose to the tumor was 70.2 Gy and areas at risk for microscopic disease received 50.4 Gy.
The spinal cord was blocked from the upper neck fields at a dose of 39.6 Gy and the blocked posterior neck was boosted to bring the dose of the blocked posterior neck field to 50 Gy. The dose to the tumor at midline, neck nodes at 1.5 cm in the midneck at the level of the thyroid cartilage, and spinal cord dose along with the central axis and supraclavicular dose at 3 cm were recorded in all cases. The minimum dose to the primary was 70.2 Gy. The dose to enlarged lymph nodes < 2 cm was 66 Gy, and > 2 cm was 70 Gy. The dose for all areas at risk for microscopic disease was 50.4 Gy. Spinal cord dose was not to exceed 45 Gy.
The spinal cord was to be shielded by a midline block in the lower neck field or a corner block in the upper neck field.
Final tumor assessment. Patients treated on the concomitant radiation/chemotherapy regimen underwent final evaluation 8 to 12 weeks after the completion of radiation. This evaluation consisted of a clinical exam by the otolaryngologist/head and neck surgeon, CT scan, or MRI to document tumor response and endoscopy. Biopsies were taken from the primary site, previously involved lymph nodes, and any other suspicious areas.
Patients who achieved clinical and pathologic complete response at the primary site had no further treatment and entered a program of close observation. Patients who had residual neoplasm verified pathologically with biopsy at the primary site had surgical resection. The resection was the original surgical resection that would have been performed at the time of initial diagnosis.
The decision regarding node dissection was made independently of the decision regarding the primary site. Patients with any clinical evidence of residual nodal involvement had an appropriate neck dissection. Patients with no evidence of clinical or pathologic disease in the regional lymph nodes did not undergo neck dissection.
Statistical Considerations
The primary outcome of interest was the histologic complete response rate for each primary tumor site, with no progression of involved nodes, after completion of induction chemotherapy followed by chemoradiotherapy. This would be interpreted as the rate of organ preservation. The study design specified that a confirmed complete histologic response rate at the primary site ≥ 50% would be of interest; further testing would not be pursued if the complete histologic response rate at the primary site was ≤ 25%. At the time of initial registration, patients were stratified by tumor site: hypopharynx versus base of tongue. Initially, 20 patients from each tumor site were accrued. If at least five complete responses at the primary site were observed, 15 additional patients would be accrued. Fourteen or more complete responses (out of 35) at the primary site would be considered as evidence warranting further study of this regimen for organ preservation, provided other factors, such as toxicity and survival, also appeared favorable. This design had a significance level (probability of falsely declaring a 20% complete response probability to warrant further study) of 4% and a power of 91%.
Assuming complete follow-up, 35 patients were sufficient to estimate the 3-year overall survival probability and 3-year progression-free survival probability to within ± 0.17 (95% CI).
As a secondary end point, organ preservation was evaluated by observing the number of patients who underwent salvage surgery at the primary site. The end point of 3-year progression-free survival with organ preservation was estimated. Using this end point, a patient was considered as a "failure" at the earliest documented time of death, progression of disease, or salvage surgery at the primary site. Assuming complete follow-up, 35 patients are sufficient to estimate the 3-year progression-free survival with organ preservation to within ± 0.17 (95% CI).
The 3-year overall survival, progression-free survival, and progression-free survival with organ preservation probabilities were estimated using the method of Kaplan and Meier.5
RESULTS
Toxicity
Treatment was tolerated well. Grade 4 toxicities (mostly hematologic) occurred in 17 of 59 patients (29%) during induction chemotherapy, and in 8 of 42 patients (19%) during concurrent chemoradiotherapy. The most common toxicities are listed in Table 2. One patient refused any concurrent chemoradiotherapy and was not assessable for toxicity during concurrent therapy. There was one death attributed to treatment, which occurred during induction chemotherapy, resulting from renal failure and sepsis.
Quality-of-life measurements, such as swallowing function, percentage of patients requiring a feeding tube or tracheostomy during long-term follow-up, and the incidence of radionecrosis, are important parameters of organ preservation to report. However, this study was not designed or funded to collect this data or to track patients for toxicities over a long period of time. Therefore this information is not available.
Induction Chemotherapy: Clinical Response at the Primary Tumor Site
Fifty-nine eligible patients were treated with induction chemotherapy (Table 3). After completion of this induction chemotherapy, patients were evaluated for local response, which was defined ≥ 50% reduction in the primary tumor. Forty-seven patients (80%) received two cycles of induction chemotherapy, and 12 patients (20%) received less than two full cycles. Forty-six patients (78%) had a > 50% response at the primary site. Forty-three of these patients went on to receive concurrent chemoradiotherapy. Three responders did not receive concurrent chemoradiotherapy: two as a result of toxicity from induction chemotherapy who subsequently received radiation alone, and the other refused any further protocol treatment.
Seven patients (12%) completed induction treatment but had < 50% response at the primary tumor site. Of those, five patients received salvage surgery, one refused surgery, and one developed incurable progressive disease.
Six patients (10%) did not complete induction chemotherapy and could not be evaluated for local response at the primary. This includes two patients who died before assessment (one due to disease, the other due to toxicity), and four who were removed from protocol treatment as a result of either toxicity (three patients) or patient noncompliance (one patient).
Chemoradiotherapy: Histologic Response at the Primary Tumor Site
The primary objective of this study was defined as the rate of complete histologic response at the primary tumor site after treatment with induction chemotherapy followed by concomitant chemoradiotherapy (Table 4). Out of 59 eligible patients enrolled, 16 patients did not receive chemoradiotherapy for reasons described in the previous section. Forty-three patients went on to receive chemoradiotherapy. Thirty-two patients (74%) received two to three cycles of chemotherapy concurrent with the radiation, five patients (12%) received less than two cycles of chemotherapy, and six patients (14%) received no chemotherapy. Thirty-two patients (54%) achieved a documented histologic complete response. There were nine additional patients who achieved a complete clinical response at the primary tumor site at time of endoscopy following the completion of chemoradiotherapy, but they did not undergo the recommended biopsies.
Two patients had residual disease after chemoradiotherapy: One had clinical residual disease at the primary site and had salvage surgery, and one patient developed metastatic disease. No biopsies were performed.
Salvage Surgery at the Primary Site at Completion of Protocol
We also looked at the results using a definition for the end point of organ preservation that included as a "success" any patient for whom salvage surgery of the primary was not necessary immediately following completion of the treatment regimen, because of excellent response to the therapy (Table 5). Using these criteria, 44 patients (75%) were classified as organ preservation success; 41 patients who required no surgery at the primary site or neck, and three patients who required a neck dissection only. The 44 patients who did not require salvage surgery included 32 patients who had histologic verification of a complete response at the primary site, nine patients who had a clinical complete response at the primary site, and the three patients who had > 50% clinical response at the primary site after induction chemotherapy, but did not receive concurrent chemoradiotherapy. One of these patients could not get more chemotherapy because of neutropenia, was treated off protocol with definitive radiation alone, and was disease-free at last contact. The second patient discontinued protocol treatment because of abdominal discomfort, was treated off protocol with radiation and cisplatin, and was disease-free at last contact. The third patient refused chemoradiotherapy after a complete response to the induction regimen, was treated off protocol with radiation alone, and was disease-free at last contact. None of those patients required salvage surgery at the date of last contact.
Nine patients did not have salvage surgery, but should not be considered successes because they either refused surgery (one patient), did not complete induction chemotherapy due to toxicity (three patients) or noncompliance (one patient) and thus were never assessed for local response, or had developed locally unresectable disease (one patient), metastases (one patient), or had died (two patients).
Six patients had salvage surgery at the time of planned assessment immediately following the end of treatment, five "early" (immediately following induction chemotherapy) and one "late" (immediately following concurrent chemoradiotherapy). Of the five patients who had early planned salvage surgery, two eventually developed local recurrence of disease and died, one developed a neck recurrence and died, and two remained free of disease. The patient who had late planned salvage surgery was alive and disease-free at date of last contact. In addition, one of the complete responders eventually received salvage surgery because of progression of disease at the primary site 8 months later, and died of cancer 16 months afterwards.
Overall, surgical salvage was performed in five (38%) of 13 patients who had < 50% response to induction chemotherapy, in one (50%) of two patients who had persistent disease after completion of chemoradiotherapy, and in the one patient who eventually had a local recurrence.
The data included in Tables 3, 4, and 5 are summarized in a flow chart in Figure 1.
Survival
All eligible patients were included in the analysis for survival, progression-free survival, and progression-free survival with organ preservation. Median follow-up for patients still alive is 51 months (50 months for base of tongue cancer patients, and 52 months for hypopharynx cancer patients).
The 3-year overall survival estimate is 64% for all patients (95% CI, 0.52 to 0.76), 67% for base of tongue (95% CI, 0.52 to 0.83), and 58% for hypopharynx (95% CI, 0.37 to 0.79; Fig 2)
The 3-year progression-free survival estimate is 57% for all patients (95% CI, 0.44 to 0.70), 62% for base of tongue (95% CI, 0.47 to 0.78), and 48% for hypopharynx (95% CI, 0.27 to 0.70; Fig 3).
The 3-year progression-free survival with organ preservation estimate is 52% for all patients (95% CI, 0.39 to 0.65), 62% for base of tongue (95% CI, 0.47 to 0.78), and 34% for hypopharynx (95% CI, 0.14 to 0.55; Fig 4).
Eighteen (39%) of the patients who had > 50% response at the primary after induction chemotherapy have eventually relapsed or died.
DISCUSSION
Our primary end point, the achievement of a histologic complete response at the primary site following chemoradiotherapy, was achieved by 54% of the patients enrolled. Additionally, another 15% of patients achieved a complete clinical response at the primary tumor site, although a biopsy confirmation was not obtained. The 64% overall survival at 3 years for the selected stage III and IV patients in our trial compares favorably to other reported data.
Surgery remains a critical treatment modality in organ preservation approaches for nonresponders and for those who experienced late locoregional failures. The 3-year survival of patients who underwent surgery in this protocol was 43% (three of seven patients), which is similar to data in a recently reported meta-analysis for salvage surgery in 1,080 patients (5-year survival = 39%).10 In the Veterans Affairs larynx1 and European Organisation for Research and Treatment of Cancer hypopharynx11 trials, the rates of surgery were 36% and 42%, respectively. However, surgical rates can be as low as 16% when cisplatin-based chemoradiotherapy is used in the larynx.12 In this protocol, 12% (seven of 59 patients) underwent surgery. Since some patients refused surgery, it is imperative that patients who are treated in an organ preservation approach are made aware that salvage surgery remains a possible therapeutic option. In this study, 58% (34 of 59 patients) had N2- or N3-stage disease. Although neck dissection in this protocol was done only for those patients with clinical residual disease, a planned neck dissection may be considered for patients who present with N2 and N3 disease if primary disease is controlled, since this may improve regional control.13
Several trials for organ preservation have included patients with base of tongue and hypopharyngeal cancer.14-17 The University of Michigan reported two sequential trials of induction chemotherapy followed by definitive radiation for patients with advanced head and neck cancer.14 Twenty-six patients had base of tongue cancer, and 34 patients had hypopharyngeal cancer. Seventy-one percent had stage IV disease; 36% had T4 tumors. After treatment was completed, 58% of those with base of tongue cancer and 59% of those with hypopharyngeal cancer were spared surgery to the primary site. Overall survival for the whole group at 3 years was 42%.
The University of Pennsylvania Cancer Center Clinical Trials Group treated 53 patients with two cycles of carboplatin and paclitaxel induction chemotherapy.17 Patients with a major response were then treated with definitive chemoradiotherapy and paclitaxel. Thirty-three patients in this group had base of tongue cancer. Organ preservation was achieved in 77% of all patients, and 3-year survival was 70%, which is similar to our results.
We are encouraged that our results provide good data demonstrating that organ preservation is achievable in a substantial number of patients with base of tongue or hypopharyngeal cancer. When we designed this phase II trial, we had anticipated proceeding to a randomized trial comparing this regimen to surgery. However, over time there has been a general trend away from surgery for these patients, in favor of chemoradiotherapy. Many potential investigators felt reluctant to participate in a trial in which patients might be assigned to surgery, without the chance for organ preservation.
In summary, our data show that this organ preservation treatment approach is feasible and tolerable for this selected group of stage III and IV patients in a multi-institutional setting. The benefit of induction chemotherapy before chemoradiotherapy is not clearly defined, and deserves further testing in a randomized setting compared with chemoradiotherapy alone. The current direction of the Southwest Oncology Group is to investigate alternative combinations of chemotherapy and radiation, and to identify molecular markers that may help select patients for the most suitable treatment modality.
Authors’ Disclosures of Potential Conflicts of Interest
NOTES
Supported in part by the following Public Health Services Cooperative Agreement grants awarded by the National Cancer Institute’s Department of Health and Human Services: CA38926, CA32102, CA27057, CA14028, CA37981, CA58416, CA03096, CA58686, CA74647.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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