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Table 1. 
Patient Characteristics at Initiation of Treatment*
Patient Characteristics at Initiation of Treatment*
Table 2. 
Patient and Treatment Details*
Patient and Treatment Details*
Table 3. 
Treatment Factors*
Treatment Factors*
1.
Phair  JP Estimating prognosis in HIV-1 infection. Ann Intern Med. 1993;118742- 744Article
2.
Balter  M New hope in HIV disease. Science. 1996;2741988- 1989Article
3.
Zhong  WGanem  D Characterization of ribonucleoprotein complexes containing an abundant polyadenylated nuclear RNA encoded by Kaposi's sarcoma–associated herpesvirus (human herpesvirus 8). J Virol. 1997;711207- 1212
4.
Mellors  JWRinaldo  CR  JrGupta  P  et al.  Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science. 1996;2721167- 1170Article
5.
Carpenter  CCFischl  MAHammer  SM  et al.  Antiretroviral therapy for HIV infection in 1997: updated recommendations of the International AIDS Society–USA Panel. JAMA. 1997;2271962- 1969Article
6.
Watkins  EBFindlay  PGelmann  ELane  HCZabell  A Enhanced mucosal reactions in AIDS patients receiving oropharyngeal irradiation. Int J Radiat Oncol Biol Phys. 1987;131403- 1408Article
7.
Costleigh  BJMiyamoto  CTMicaily  BBrady  LW Heightened sensitivity of the esophagus to radiation in a patient with AIDS. Am J Gastroenterol. 1995;90812- 814
8.
Berson  A Radiation therapy for malignancies in the setting of HIV disease: discussion. Oncology. 1997;11701- 702
9.
Valerie  KLaster  WSKirkham  JCKuemmerle  NB Ionizing radiation activates nuclear factor κ B but fails to produce an increase in human immunodeficiency virus gene expression in stably transfected human cells. Biochemistry. 1995;3415768- 15776Article
10.
Not Available, HIV infection, principles of therapy, NIH panel report, and HIV-infected adults, antiretroviral agents use, guidelines, 62 Federal Register. 33417- 33418 June19 1997;
11.
Voelker  R Protease inhibitors bring new social, clinical uncertainties to HIV care. JAMA. 1997;2771182- 1184Article
12.
Moore  PSBoshoff  CWeiss  RA  et al.  Molecular mimicry of human cytokine and cytokine response pathway genes by KSHV. Science. 1996;2741739- 1744Article
13.
Boshoff  CEndo  YCollins  PD  et al.  Angiogenic and HIV-inhibitory functions of KSHV-encoded chemokines. Science. 1997;278295- 298Article
Original Article
August 1999

Oral Cavity and Oropharyngeal Tumors in Human Immunodeficiency Virus–Positive PatientsAcute Response to Radiation Therapy

Author Affiliations

From the Departments of Radiation Oncology (Dr Kao and Ms Devine) and Otolaryngology and Head and Neck Surgery (Dr Mirza), Philadelphia Veterans Affairs Medical Center, Philadelphia, Pa.

Arch Otolaryngol Head Neck Surg. 1999;125(8):873-876. doi:10.1001/archotol.125.8.873
Abstract

Background  The survival of patients with human immunodeficiency virus (HIV) has improved considerably with modern medical management. However, there remains surprisingly little information on treating head and neck neoplasms in HIV-positive patients.

Objective  To report our recent experience treating oral cavity and oropharyngeal tumors in HIV-positive patients.

Design and Patients  Retrospective analysis of a cohort of 8 HIV-positive patients with Kaposi sarcoma (KS), lymphoma, or squamous carcinoma of the oral cavity or oropharynx who were consecutively treated during a single year with radiation therapy at a tertiary care referral center. Length of follow-up was at least 2 years (mean, 2.5 years).

Results  All patients had partial and complete responses to treatment lasting until the last follow-up. However, we found that treatment was considerably better tolerated by patients with non-KS tumors, with fewer acute reactions and significantly less weight loss, despite larger treatment volumes and higher radiation doses, compared with patients with KS. Patients with non-KS tumors received a mean radiation dose of 62.6 Gy to 2636 cm3, yet lost only a mean of 0.1 kg in weight, whereas patients with KS were treated with a mean radiation dose of 19 Gy to a mean volume of 568 cm3, but lost a mean of 5.8 kg during treatment (P=.005) and on average sustained an additional grade of severity on a standard scale of mucosal reaction (P=.01).

Conclusions  Oral cavity and oropharyngeal tumors in HIV-positive patients respond to radiation therapy, but there is a marked difference in the degree of acute reactions to treatment between patients with and without KS. Infection with HIV is not a contraindication when aggressive radiation therapy is needed in select patients.

THE LIFE expectancy of patients infected with the human immunodeficiency virus (HIV) has improved considerably in recent years due to advances in medical management, including the development of protease inhibitors and purine nucleoside analogs.1,2 Despite this remarkable progress, there is surprising little information on the treatment of head and neck neoplasms other than Kaposi sarcoma (KS) in HIV-infected patients. As more and more HIV-infected patients enjoy prolonged survival and become candidates for aggressive curative therapy, an increasing proportion of patients may not only be surgical candidates, but also may benefit from radiation therapy.

The treatment of oral cavity and oropharyngeal tumors in HIV-positive patients has acquired a reputation for being difficult, likely because of the experience with treating patients with mucosal KS. Treatment of patients with KS frequently is characterized by brisk mucositis even at relatively low doses of radiation. In the past several years, however, considerable insight on the pathophysiological features of KS has developed. There is accumulating evidence that links KS with human herpesvirus 8 (HHV8).3 Patients with non-KS neoplasms, if not likewise infected with HHV8, also may not necessarily be at the same risk for such side effects.

We conducted a study of consecutive HIV-positive patients at the Philadelphia Veterans Affairs Medical Center, Philadelphia, Pa. We assessed the patient tolerance of radiation therapy and treatment results.

MATERIALS AND METHODS

The study population was drawn from all patients receiving treatment in the Department of Radiation Oncology from January 1 through December 31, 1994. This period was selected to allow for at least 2 years of follow-up. During this period, 8 patients who were infected with HIV were treated for oral cavity or oropharyngeal cancers, 4 with non-KS tumors and 4 with KS (Table 1). All patients were receiving antiviral as well as antifungal medication throughout the radiation therapy (Table 2). At the time the patients were undergoing treatment, protease inhibitors were not yet available. Data were recorded for patient age and sex, date of diagnosis, and tumor site and histological characteristics. Additional information was taken regarding medication, surgical treatment, radiation field size and dose, pretreatment and posttreatment weight, and tumor response. After the initiation of radiation therapy, the radiation oncologist evaluated the progress and tolerance of each patient at least weekly. Each patient was also observed regularly after the completion of radiation therapy, and all patients were available for follow-up. The mean length of follow-up was 2.5 years.

Treatment consisted of megavoltage radiation usually delivered via opposing lateral fields to encompass the target area, except for a patient with KS who was treated via orthovoltage radiation. Radiation treatment volume was defined as the product of the treatment field size and the separation. Mucositis was graded according to the Radiation Therapy Oncology Group Acute Radiation Morbidity Scoring Criteria for Mucous Membranes. This scale defines the following scores: 0 indicates no change compared with baseline; 1, injection site may produce mild pain not requiring analgesic; 2, patchy mucositis that may produce an inflammatory serosanguineous discharge and may include moderate pain requiring analgesia; 3, confluent fibrinous mucositis that may include severe pain requiring narcotic; and 4, ulceration, hemorrhage, or necrosis. Complete response for KS was defined as complete flattening of lesions or cessation of bleeding. Complete response for non-KS tumors was defined as absence of clinical evidence of tumor, whereas partial response was defined as decrease in tumor volume of greater than 40%.

Statistical analysis was performed using commercially available software (SPSS [SPSS Inc, Chicago, Ill]; and Microsoft Excel [Microsoft, Redmond, Wash]). Differences between population means were determined using analysis of pooled-variance confidence levels. Statistical significance was defined as P=.05.

RESULTS

At initiation of radiation therapy, patients treated for non-KS tumors appeared comparable with those treated for KS in terms of age, hemoglobin level, and weight, but had higher CD4+ counts (Table 1). However, patients with non-KS tumors tolerated treatment considerably better than patients with KS, with fewer acute reactions and significantly less weight loss, despite receiving larger treatment volumes and higher doses (Table 3). Patients with non-KS tumors received a mean radiation dose of 62.2 Gy to 2636 cm3, yet lost only a mean of 0.1 kg of weight, whereas patients with KS received a mean radiation dose of 19.0 Gy to a mean volume of 563 cm3, but lost a mean of 5.8 kg during treatment (P=.005). Patients with KS sustained on average an additional grade of severity on the standard scale of mucosal reaction (P=.01) (Table 2). No correlation between CD4+ count and tolerance was noted. There were no significant differences in changes of hemoglobin and CD4+ counts during treatment in the 2 groups.

Response to treatment was noted in all patients, with complete resolution of the treated lesions in all patients with KS and at least a partial response in the patients with non-KS lesions. These responses were durable and lasted until death or last follow-up. For example, patient 5 presented with a 3-cm squamous cell carcinoma on the floor of the mouth with bilateral 1- to 2-cm upper neck lymph nodes. He was treated aggressively with 72.0 Gy of radiation and was able to complete the prescribed course without the need for a treatment break. By the end of his treatment, the primary tumor as well as his neck lymphadenopathy had completely resolved. He was free of disease at his last follow-up more than 3 years after completion of treatment. Patient 6 was treated for an extensive squamous cell carcinoma completely filling the tonsillar fossa, extending anteriorly to involve the retromolar trigone, infiltrating deeply to involve the masseter muscles, and resulting in trismus. This patient was able to complete the prescribed course of radiation therapy without the need for treatment break as well as maintain his weight; by the end of treatment the tumor had shrunk considerably, and the trismus had resolved. Unfortunately, the patient died of a cardiac event 2 years after treatment. At the last follow-up, the tumor was still evident as an ulceration in the tonsillar fossa, but the patient was able to chew without substantial discomfort.

At last follow-up, 4 patients had died, including patient 6. The 3 other patients who died were all treated for KS and died of multiple-system failure related to progression of the HIV infection and probably not directly attributable to the oral cavity or oropharyngeal KS or the local radiation.

COMMENT

We found that patients who were positive for HIV were able to tolerate relatively high doses of radiation for non-KS malignant neoplasms without the need for treatment breaks and with excellent control of tumor. In contrast, patients treated for KS sustained significant morbidity during treatment, despite lower doses of radiation. These findings suggest that appropriately selected HIV-infected patients may be able to tolerate and benefit from aggressive definitive treatment of non-KS malignant neoplasms.

Our findings may be especially pertinent, given that with present-day medical management, including new and more effective antiretroviral treatment and protease inhibitors, HIV-infected patients may expect to live longer and to enjoy a higher quality of life.2,4,5 Increased public awareness of HIV-related issues also may result in increasingly earlier diagnosis and treatment of HIV, as well as earlier diagnosis of HIV-associated malignant neoplasms. The combination of earlier diagnosis and patients in better overall medical condition thus may lead to a higher proportion of patients being curative candidates who would benefit from aggressive treatment.

Kaposi sarcoma is the most common acquired immunodeficiency syndrome–related neoplasm, and there is considerable literature on the morbidity often encountered in treating oropharyngeal KS with radiation. For example, our experience in treating patients with head and neck mucosal KS is consistent with that reported by Watkins et al.6 We found that our patients on average lost 5.8 kg of weight during treatment, despite relatively modest radiation doses. Watkins et al likewise found that mucositis severe enough to require treatment break after administration of only 12.0 Gy of radiation developed in 4 of 8 patients with oropharyngeal KS.

However, there is a striking paucity of information on the radiation therapy for non-KS oral cavity and oropharyngeal malignant neoplasms. It is perhaps unsurprising that, because of this vacuum of information, the experience with treating head and neck mucosal KS is often generalized to apply to the treatment on non-KS tumors. Our results suggest that, with present-day medical management of HIV infection, this generalization may not be valid. One case report noted early esophageal stricture in an HIV-positive patient receiving radiation therapy for a massive mediastinal adenocarcinoma with associated lymphadenopathy; the authors speculated that the patient's endarteritis and the strong possibility of tumor infiltration into the esophagus may have contributed to this development.7 There has also been a nonpublished report of poor tolerance by HIV-positive patients with laryngeal squamous cell carcinomas treated with surgery and/or radiation therapy,8 but details regarding the treatment delivered remain unclear, and it is unknown whether these patients had opportunistic infections that may have interfered with treatment. We speculate that the success and excellent tolerance of our patients in contrast may be attributable at least in part to recent advances in medical management of HIV infection. Although none received protease inhibitors (which were not yet available at the time of their treatment), all were receiving zidovudine and prophylactic antifungal therapy and undergoing meticulous monitoring of blood cell counts. Select patients may not be able to tolerate larger radiation fields or doses higher than those used in our study. The possibility that radiation in itself results in immunosuppression and increased HIV activity has been raised,9 although we did not observe evidence of this in our patients.

Treatment of HIV-infected patients is evolving quickly. With the development of new therapies, guidelines issued by the US Department of Health and Human Services now call for combination treatment of all HIV-infected patients with CD4+ cell counts of less than 0.5×109/L (or >14-24 HIV RNA copies/mL) with 3 drugs that include a protease inhibitor in the initial regimen.10,11 The recent identification of KS-associated herpesvirus—commonly referred to as HHV8—in most KS lesions gives additional insight into the pathophysiological features of toxic effects noted with treatment of KS. It also remains to be determined whether HHV8 has effects on oropharyngeal mucosa in ways akin to herpes simplex virus types 1 and 2. Human herpesvirus 8 has been found to encode for a number of viral proteins mimicking the actions of human cytokines, macrophage inflammatory protein chemokines, and other factors, which can potentially stimulate not only angiogenesis but inflammation as well.12,13

Clearly, more data are needed to verify and extend our observations. It remains to be determined whether there are subsets of HIV-infected patients with non-KS head and neck malignant neoplasms who may expect higher morbidity with treatment than the patients described herein. Such data would enable us to determine the optimal treatment for HIV-infected patients in maximizing the chances for cure while minimizing morbidity.

CONCLUSIONS

We found that patients positive for HIV infection who received radiation therapy for non-KS tumors tolerated treatment surprisingly well and derived excellent responses. The patients with KS also responded, but treatment was marked by a significantly greater degree of mucositis and weight loss, despite significantly smaller treatment fields and doses. These observations suggest that HIV infection alone is not a contraindication when aggressive radiation therapy is needed in selected patients.

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Article Information

Corresponding author: Gary D. Kao, MD, PhD, Hospital of the University of Pennsylvania, Department of Radiation Oncology, 2 Donner, 3400 Spruce St, Philadelphia, PA 19104 (e-mail: kao@xrt.upenn.edu).

Accepted for publication December 9, 1998.

References
1.
Phair  JP Estimating prognosis in HIV-1 infection. Ann Intern Med. 1993;118742- 744Article
2.
Balter  M New hope in HIV disease. Science. 1996;2741988- 1989Article
3.
Zhong  WGanem  D Characterization of ribonucleoprotein complexes containing an abundant polyadenylated nuclear RNA encoded by Kaposi's sarcoma–associated herpesvirus (human herpesvirus 8). J Virol. 1997;711207- 1212
4.
Mellors  JWRinaldo  CR  JrGupta  P  et al.  Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science. 1996;2721167- 1170Article
5.
Carpenter  CCFischl  MAHammer  SM  et al.  Antiretroviral therapy for HIV infection in 1997: updated recommendations of the International AIDS Society–USA Panel. JAMA. 1997;2271962- 1969Article
6.
Watkins  EBFindlay  PGelmann  ELane  HCZabell  A Enhanced mucosal reactions in AIDS patients receiving oropharyngeal irradiation. Int J Radiat Oncol Biol Phys. 1987;131403- 1408Article
7.
Costleigh  BJMiyamoto  CTMicaily  BBrady  LW Heightened sensitivity of the esophagus to radiation in a patient with AIDS. Am J Gastroenterol. 1995;90812- 814
8.
Berson  A Radiation therapy for malignancies in the setting of HIV disease: discussion. Oncology. 1997;11701- 702
9.
Valerie  KLaster  WSKirkham  JCKuemmerle  NB Ionizing radiation activates nuclear factor κ B but fails to produce an increase in human immunodeficiency virus gene expression in stably transfected human cells. Biochemistry. 1995;3415768- 15776Article
10.
Not Available, HIV infection, principles of therapy, NIH panel report, and HIV-infected adults, antiretroviral agents use, guidelines, 62 Federal Register. 33417- 33418 June19 1997;
11.
Voelker  R Protease inhibitors bring new social, clinical uncertainties to HIV care. JAMA. 1997;2771182- 1184Article
12.
Moore  PSBoshoff  CWeiss  RA  et al.  Molecular mimicry of human cytokine and cytokine response pathway genes by KSHV. Science. 1996;2741739- 1744Article
13.
Boshoff  CEndo  YCollins  PD  et al.  Angiogenic and HIV-inhibitory functions of KSHV-encoded chemokines. Science. 1997;278295- 298Article
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