Treatment of advanced oropharyngeal cancers with chemotherapy and radiation. (Original Article).

Abstract

We conducted a retrospective chart review of treatment outcomes in 17 adults who had been selected to undergo concomitant chemotherapy and radiation (chemo/XRT) for late-stage oropharyngeal cancers. All patients had been treated at the West Los Angeles VA Medical Center between March 1, 1998, and Sept. 30, 2000. Nine patients had a primary tumor at the base of the tongue, five had a primary tumor in the tonsillar area, and three had a tumor that affected both sites. Of this group, 15 patients completed one to three cycles of chemo/XRT, and the remaining two died during therapy. At the most recent follow-up, 9 of the 17 patients (52.9%) were documented to still be alive; seven patients had earlier died as a result of their primary tumor or a distant metastasis, and one patient had been lost to follow-up after completing treatment. At study 'send, the duration of post-treatment survival ranged from 2 to 36 months (mean: 12.5). Based on the results of our small series, we conclude that chemo/XRT is a valid alter native to surgery with postoperative radiation and to radiation alone. Chemo/XRT yields acceptable rates of local control and allows for organ preservation with tolerable side effects.

Introduction

Some 30% of head and neck cancers occur in the oropharynx, and otolaryngologists diagnose more than 30,000 such cases each year. (1) In the past, patients with oropnaryngeal cancers have been classified into two general categories: those who are surgically salvageable and those who are not. The standard treatment for patients whose cancers are surgically resectable includes radiotherapy in addition to surgery. (2) Those who cannot be operated on are generally treated with radiation alone.

Because surgery can lead to significant morbidity and loss of organ function, there is a need for an alternate treatment. (3) In this article, we describe our study of the effect of concomitant chemotherapy and radiation (chemo/XRT) on survival in patients with advanced oropharyngeal cancers. We also discuss outcomes in terms of morbidity and preservation of organ function.

Patients and methods

We performed a retrospective chart review of 17 patients who had been chosen to undergo chemo/XRT for the treatment of advanced-stage oropharyngeal cancers at the West Los Angeles VA Medical Center between March 1, 1998, and Sept. 30, 2000. These patients had been diagnosed on the basis of physical examination, panendoscopy, and advanced imaging studies (computed tomography and magnetic resonance imaging). All patients had been staged in accordance with the current recommendations of the American Joint Committee on Cancer (AJCC). (4) Prior to treatment, each case was discussed at a meeting of a multidisciplinary head and neck tumor panel, and all patients underwent a dental evaluation.

The reasons that patients had been offered chemo/XRT rather than surgery with postoperative radiation were varied. Some patients were deemed to have unresectable tumors, some were poor surgical candidates because of their overall medical condition, and one had refused to undergo surgery. The criteria for establishing disease as unresectable were (1) an invasion of a tumor into the prevertebral fascia or skull base, (2) tumor fixation to the carotid artery, and (3) the presence of a distant metastasis. Follow-up information was obtained from our center's electronic medical record system.

Results

At their first visit, the 17 patients, all men, ranged in age from 46 to 73 years (mean: 56.9) (table 1). Eleven were white and six were black. Nine patients had a primary tumor at the base of the tongue, five had a primary tumor in the tonsillar area, and three had a tumor that affected both sites. Tumor sizes ranged from T1 to T4, and nodal status ranged from NO to N3. All patients were staged according to AJCC criteria; 16 were classified as stage IV and one was classified as stage II.

Fifteen of the 17 patients completed their chemo/XRT regimen as prescribed. The other two patients died during treatment. The number of treatment cycles ranged from 1 to 3 (mean: 1.85).

Chemotherapy. Thirteen patients received a chemotherapeutic combination of cisplatin and 5-fluorouracil. This regimen involved a continuous infusion of cisplatin (100 mg/[m.sup.2]) on days 1 and 29 and a continuous infusion of 5-fluorouracil (1,000 mg/[m.sup.2]) on days 1 through 4 and 29 through 32. Of the remaining four patients, one received cisplatin alone, one received cisplatin and etoposide, one received paclitaxel (175 mg/[m.sup.2]) and 5-fluorouracil, and one received paclitaxel and carboplatin (300 mg/[m.sup.2]).

Radiotherapy. A 6-MeV linear accelerator was used to deliver radiation to all patients. Radiation to opposed lateral fields was used to treat the primary tumors, and electronbeam boosts were delivered to selected nodal regions. The total number of treatments delivered to individual patients ranged from 7 to 40. Daily radiation was delivered in a single 200-cGy dose; the mean total tumor dose delivered over a 6- to 7-week period was 6,197 cGy.

Survival. Responses to chemo/XRT varied, and at study's end, survival times ranged from 2 to 36 months (mean: 12.5). At the most recent follow-up, 9 of the 17 patients (52.9%) were documented to still be alive. Among the others, 1 patient who survived chemo/XRT was lost to follow-up; 5 patients died following treatment as a result of either their primary tumor or a metastasis to the lung, bone, or liver; and 2 others died during treatment.

Organ preservation. Among the 17 patients, oropharyngeal function was preserved in all 12 (70.6%) who survived the full course of treatment.

Morbidity. The most common side effects of treatment were stomatitis and dysphagia/odynophagia (table 2). In addition, five patients required a gastrostomy tube during chemo/XRT. One patient required a tracheostomy tube placement for respiratory distress during treatment, and he died shortly thereafter.

Discussion

The success of chemo/XRT protocols for organ preservation in patients with laryngeal cancers has led to an increase in the use of these protocols for nonlaryngeal head and neck squamous cell disease. Many previous studies have addressed the use of chemo/XRT for both laryngeal and nonlaryngeal squamous cell cancers, but the use of chemo/XRT as a definitive treatment specifically for advanced oropharyngeal cancers has not been well studied.

Many variables must be taken into consideration in reviewing the results of treatment for oropharyngeal cancers. Cancers at different sites in the oropharynx (i.e., the tonsils and the base of the tongue) can respond differently to treatment. The response to treatment of cervical metastases is also different from the response of primary tumors. Because our current staging system reflects a combination of T and N stages, it is often difficult to determine whether treatment protocols for advanced-stage cancers are effective specifically for primary sites or nodal metastases.

In a series of patients with cancer of the base of the tongue, Gourin and Johnson found that overall control rates following surgery with postoperative radiation ranged from 72 to 92%. (5) In a study of patients with oropharyngeal cancers, Zelefsky et al reported an overall 7-year survival rate of 52% and a disease-free control rate of 64%. (6) In patients with stage IV cancers of the head and neck following chemo/XRT, Yokes et al found that the locoregional control rate was 92% and overall survival was 55% (median follow-up: 38 mo). (7) Calais et al reported a 3-year survival rate of 42% among patients with oropharyngeal cancers in the chemo/XRT arm of their study. (8) Nathu et al found a 63% local control rate for oropharyngeal cancers after 5 years. (9) Poole et al demonstrated local control rates of 71 and 60% in primary oropharyngeal tumors and cervical node metastases, respectively. (10)

In our small study of patients with stage II to IV cancers of the oropharynx, the initial local and regional control rate was 88%. At 12 months, our local control rate dropped to 70%, and at 24 months, it was less than 60%. These rates are consistent with those reported in earlier studies of chemo/XRT and in studies of surgery with postoperative radiation.

The morbidity experienced by patients who undergo surgery with postoperative radiation is significantly different from that experienced by patients who undergo chemo/XRT. The side effects of surgery with postoperative radiation can significantly compromise quality of life. These side effects can be categorized as early and late morbidities. Early morbidities are often related to the surgery itself, and they include nerve deficits, flap failures, early and delayed wound infections, and complicadons of anesthesia. Late morbidities include strictures and osteoradionecrosis. Surgery can also complicate the detection of recurrences. (11)

Side effects of postoperative radiation include severe stomatitis, xerostomia, and malnutrition serious enough to necessitate the placement of a gastrostomy tube. Moreover, surgery with postoperative radiation can also compromise organ function. Patients who undergo resection of a stage IV lesion of the tonsil or base of the tongue frequently experience numerous problems in their attempts to carry on normal activities of daily living. Such problems include inabilities to speak intelligibly, to chew and maintain a regular diet, and to eat in public without embarrassment.

The most common early complications associated with chemo/XRT in our study were stomatitis, dysphagia! odynophagia, and the need for gastrostomy tube placement. The extent of these morbidities had decreased greatly by the 12- and 24-month follows-ups.

Our data suggest that patients with advanced-stage oropharyngeal cancers should be offered the option of being treated with chemo/XRT. In our small series, locoregional control rates following chemo/XRT were similar to those that have been reported following surgery with postoperative radiation. In addition, organ preservation was achieved with an acceptable degree of morbidity.

Table 1

Patient and tumor characteristics (n = 17)

                            Pts w/unresectable  Organ-preservation
Characteristic                    tumors               pts

Sex
 Male                               7                   10
 Female                             0                   0

Age
 Mean                              56.7                57.1
 Range                           46 to 73            46 to 64

Race
 White                              6                   5
 Black                              1                   5

Site of primary tumor
 Base of the tongue                 5                   4
 Tonsillar area                     1                   4
 Both                               1                   2

Tumor size
 TX                                 0                   0
 T0                                 0                   0
 T1                                 0                   1
 T2                                 0                   4
 T3                                 4                   2
 T4                                 3                   3

Lymph node status
 N0                                 0                   1
 N1                                 1                   1
 N2a                                0                   4
 N2b                                3                   3
 N2c                                3                   0
 N3                                 0                   1

Stage
 I                                  0                   0
 II                                 0                   1
 III                                0                   0
 IV                                 7                   9

Type of chemotherapy
 Cisplatin/5-fluorouracil           4                   9
 Cisplatin alone                    1                   0
 Cisplatin/etoposide                1                   0
 Paclitaxel/5-fluorouracil          0                   1
 Paclitaxel/carboplatin             1                   0

Cycles
 Mean                              1.7                 2.0
 Range                            1 to 3              1 to 2

Radiation dose (cGy)
 Mean                             5,593               6,801
 Range                         200 to 7,020       1,260 to 7,200


Characteristic                 Total

Sex
 Male                            17
 Female                          0

Age
 Mean                           56.9
 Range                        46 to 73

Race
 White                           11
 Black                           6

Site of primary tumor
 Base of the tongue              9
 Tonsillar area                  5
 Both                            3

Tumor size
 TX                              0
 T0                              0
 T1                              1
 T2                              4
 T3                              6
 T4                              6

Lymph node status
 N0                              1
 N1                              2
 N2a                             4
 N2b                             6
 N2c                             3
 N3                              1

Stage
 I                               0
 II                              1
 III                             0
 IV                              16

Type of chemotherapy
 Cisplatin/5-fluorouracil        13
 Cisplatin alone                 1
 Cisplatin/etoposide             1
 Paclitaxel/5-fluorouracil       1
 Paclitaxel/carboplatin          1

Cycles
 Mean                           1.85
 Range                         1 to 3

Radiation dose (cGy)
 Mean                          6,197
 Range                      200 to 7,200

Table 2

Complications of chemo/XRT in the 17 patients

Complication            n (%)

Stomatitis             8 (47.1)
Dysphagia/odynophagia  5 (29.4)
Gastrostomy            5 (29.4)
Xerostomia             2 (11.8)
Overall deterioration  2 (11.8)
Tracheostomy           1 (5.9)

References

(1.) Correa AJ, Burkey BB. Current options in management of head and neck cancer patients. Med Clin North Am 1999;83:235-46.

(2.) Forastiere AA, Trotti A. Radiotherapy and concurrent chemotherapy: A strategy that improves locoregional control and survival in oropharyngeal cancer. J Nati Cancer Inst 1999;91:2065-6.

(3.) Kokubo M, Nagata Y, Nishimura Y, et al. Concurrent chemoradiotherapy for oropharyngeal carcinoma. Am J Clin Oncol 2001;24:71-6.

(4.) American Joint Committee on Cancer. AJCC Cancer Staging Handbook. 5th ed. Philadelphia: Lippincott-Raven, 1998:38-9.

(5.) Gourin CG, Johnson JT. Surgical treatment of squamous cell carcinoma of the base of tongue. Head Neck 2001;23:653-60.

(6.) Zelefsky MJ, Harrison LB, Armstrong JG. Long-term treatment results of postoperative radiation therapy for advanced stage oropharyngeal carcinoma. Cancer 1992;70:2388-95.

(7.) Vokes EE, Kies MS, Haraf DJ, et al. Concomitant chemoradiotherapy as primary therapy for locoregionally advanced head and neck cancer. J Clin Oncol 2000;18:1652-61.

(8.) Calais G, Alfonsi M, BardetE, et al. Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Nati Cancer Inst 1999;91:2081-6.

(9.) Nathu RM, Mendenhall WM, Parson JT, et al. Induction chemotherapy and radiation therapy for T4 oropharyngeal carcinoma. Radiat Oncol Investig 1999;7:98-105.

(10.) Poole ME, Sailer SL, Rosenman JG, et al. Chemoradiation for locally advanced squamous cell carcinoma of the head and neck for organ preservation and palliation. Arch Otolaryngol Head Neck Surg 2001;127:1446-50.

(11.) Adelstein DJ, Saxton JP, Lavertu P, et al. A phase III randomized trial comparing concurrent chemotherapy and radiotherapy with radiotherapy alone in resectable stage III and IV squamous cell head and neck cancer: Preliminary results. Head Neck 1997;19:567-75.

From the Division of Head and Neck Surgery, Department of Surgery, David Geffen School of Medicine, University of California Los Angeles (Dr. LoTempio and Dr. Wang): and the Department of Surgery (Dr. LoTempio and Dr. Wang) and the Department of Radiation Oncology (Dr. Sadeghi), the VA Greater Los Angeles Health Care System.

Reprint requests: Marilene B. Wang, MD, Division of Head and Neck Surgery, UCLA School of Medicine, 10833 Le Conte Ave., Los Angeles, CA 90095-1624. Phone: [phone]; fax: [phone]; e-mail: [e-mail]

Originally presented during the annual Western Section meeting of the Triological Society; Feb. 1-3, 2002; Pasadena, Calif.