Volume 77, Issue 5 , Pages 1375-1379, 1 August 2010
Toxicity of Head-and-Neck Radiation Therapy in Human Immunodeficiency Virus–Positive Patients
Article Outline
Purpose
To examine the acute morbidity of high dose head and neck RT and CRT in patients with infected with HIV.
Methods and Materials
All HIV-positive patients who underwent radiation therapy for head and neck cancer in our department between 2004 and 2008 were reviewed. Treatment related data were examined. All treatments were delivered with megavoltage photon beams or electron beams. Patients were evaluated by an attending radiation oncologist for toxicity and response on a weekly basis during therapy and monthly after treatment in a multidisciplinary clinic. Acute toxicities were recorded using the Radiation Therapy and Oncology Group (RTOG) common toxicity criteria. Response to treatment was based on both physical exam as well as post-treatment imaging as indicated.
Results
Thirteen patients who underwent RT with a diagnosis of HIV were identified. Median age was 53 years and median follow-up was 22 months. Twelve had squamous cell carcinoma and one had lymphoproliferative parotiditis. Median radiation dose was 66.4 Gy and median duration of treatment was 51 days. The median number of scheduled radiotherapy days missed was zero (range 0 to 7). One patient (8%) developed Grade 4 confluent moist desquamation. Eight patients (61%) developed Grade 3 toxicity.
Conclusion
Based on our results, HIV-positive individuals appear to tolerate treatment for head and neck cancer, with toxicity similar to that in HIV-negative individuals.
Head and neck cancer, Radiation toxicity, HIV, Mucositis, Morbidity
Introduction
Highly active antiretroviral treatment (HAART) has resulted in longer survival for individuals infected by human immunodeficiency virus (HIV). Consequently, these patients are developing tumors that were previously rare. Between 1990 and 2000, when HAART was widely adopted in the United States, the incidence of cancers not associated with aquired immune deficiency sydrome (AIDS), including tumors of the oral cavity and pharynx, has increased dramatically (1), and similar findings have been observed in Europe (2). However, optimal cancer treatment in this population is unclear. Radiation therapy (RT) in HIV-positive patients has resulted in profound toxicity for certain tumors, namely anal and cervical cancer 3, 4. Gicanchi et al. reported Grade 3 to 4 toxicity in 53% of HIV-positive patients receiving RT for cervical cancer, which was sevenfold higher than in those not infected with HIV. Similarly, in anal cancer, hematologic and cutaneous toxicities are more pronounced in HIV-positive patients, and these often result in treatment interruptions or other modifications in therapy (5).
Given the rarity of head and neck cancer in HIV-positive individuals, the treatment tolerance of aggressive treatment is unclear. Use of RT confers significant acute toxicity in most patients with head-and-neck cancer, mainly oral mucositis (6). Data on mucosal tolerance in the setting of HIV are limited, but patients with oral Kaposi's sarcoma (KS) have experienced pronounced mucosal toxicity with RT doses of 15 to 30 Gy (7). Based on these observations, even greater morbidity could be anticipated in HIV- positive patients treated for head and neck cancer, in whom doses of 60 to 70 Gy are used and management of locally advanced disease often requires intensification with accelerated fractionation RT (AFRT) or concurrent chemoradiation (CRT). Kao et al., however, found that tolerance to RT in non-KS patients was significantly better than in patients with oral KS despite higher doses and larger treatment volumes. The authors postulated that this could be caused by differences in mucosal pathophysiology in patients affected by KS (8). Because oral malignancies in HIV-positive individuals are becoming more common, information is needed on the capacity of HIV-positive patients to tolerate intensive RT and CRT for proper management of their malignancy. The purpose of this study was to examine the acute morbidity of intensive head-and-neck RT and CRT in patients infected with HIV.
Methods and Materials
Approval from Institutional Review Board of New York University School of Medicine was obtained for this retrospective study. All patients who received radiation therapy to the head and neck in our department between 2004 and 2008 were reviewed. From that population, HIV-positive patients were identified. Treatment-related data that were examined included the patient age, diagnosis, stage, site of disease, treatment technique (three-dimensional conformal RT [3D-CRT] or intensity-modulated radiation therapy [IMRT]), photon energy, total dose, whether the neck was irradiated, use of concurrent chemotherapy, duration of radiation treatment, number of radiation treatment days missed, amount of weight loss, response to therapy, and site of recurrence. HIV-related information that was examined included viral load and CD4+ cell count.
All treatments were delivered with megavoltage photon beams or electron beams. Patients were evaluated by an attending radiation oncologist for toxicity and response on a weekly basis during therapy and monthly after treatment in a multidisciplinary clinic. Acute toxicities were recorded using the Radiation Therapy and Oncology Group (RTOG) common toxicity criteria. Response to treatment was based on both physical examination as well as posttreatment imaging as indicated.
Results
Thirteen patients who underwent RT with a diagnosis of HIV were identified. The median age was 53 years (range, 42–65 years), and the median follow-up was 22 months (range, 13–34 months). Twelve patients were treated for squamous cell carcinoma (6 oropharynx, 3 supraglottic larynx, 1 oral tongue, 1 paranasal sinus, and 1 skin cancer of the face). One patient was treated for lymphoproliferative parotid hyperplasia. Stages of the 12 patients with malignancy were as follows: Stage I, 1 patient, Stage II, 1 patient; Stage III, 3 patients; Stage IV, 6 patients; and recurrent, 1 patient (Table 1). All patients except 1 were receiving HAART at the time of RT. CD4+ lymphocyte counts and viral load data were available for 7 patients. The median CD4+ count was 201 cells/mm3 (range, 125–458 cells/mm3), and the median viral load was less than 50 copies/ml (range, undetectable to 46,600 copies/ml). Specifically, 1 patient had an undetectable viral load, 4 patients had levels less than 50 copies/ml, 1 had 174 copies/ml, 1 had 2,786 copies/ml, and the 1 patient not receiving HAART had a viral load of 46,600 copies/ml (Table 2).
Table 1. Characteristics of the head-and-neck radiation therapy patients (n = 13)
| Age (y) | |
 Range | 42–65 |
| Median | 53 |
| Sex | |
| Male | 9 |
| Female | 4 |
| Histology | |
| Squamous cell carcinoma | 12 |
| Lymphoproliferative parotiditis | 1 |
| Site | |
| Oropharynnx | 6 |
| Supraglottic larynx | 3 |
| Oral tongue | 1 |
| Paranasal sinus | 1 |
| Skin (face) | 1 |
| Parotid | 1 |
| Stage | |
| I | 1 |
| II | 1 |
| III | 3 |
| IV | 6 |
| Recurrent | 1 |
Table 2. Laboratory HIV markers in study patients
| CD4+ (cells/mm3) | |
|---|---|
| Median | 201 |
| Range | 125–458 |
| Viral load (copies/ml) | |
| Median | <50 |
| Range | Undetectable to 46,600 |
The median RT dose delivered was 66.4 Gy (range, 20–70 cGy; 20 Gy was prescribed for lymphoproliferative parotid hyperplasia). One patient was treated with electron beam therapy, 6 were treated with three-dimensional conformal photons, and 6 were treated with IMRT. One patient was treated with an altered fractionation regimen uing a concomitant boost followed by neck dissection, and 6 patients received concurrent chemotherapy with RT. Patients who underwent CRT were prescribed intravenous cisplatin (100 mg/m2, days 1, 22, and 43 of RT). Treatment volumes for the 12 patients with SCC included 10 patients treated to the primary and bilateral neck lymphatics, 1 treated with electrons to the primary site only for SCC skin, and 1 treated to the primary only with IMRT for T1Nx SCC of the ethmoid sinus. The median treatment duration was 51 days (range, 15–61 days), and the median number of scheduled radiotherapy days missed was zero (range, 0–7) (Table 3).
Table 3. Radiation therapy dose, technique, duration, and days missed in study patients
| Dose (Gy) | |
| Median | 66.4 |
| Range | 20–70 |
| Technique (no. of patients) | |
| Electron beam | 1 |
| 3-D conformal photons | 6 |
| IMRT | 6 |
| Duration of treatment (days) | |
| Median | 51 |
| Range | 15–61 |
| Treatment days missed | |
| Median | 0 |
| Range | 0–7 |
One patient (8%) developed Grade 4 confluent wet desquamation. Eight patients (61%) developed Grade 3 toxicity: 2 patients had Grade 3 mucositis and dermatitis, 4 patients developed only Grade 3 mucositis, and 2 patients had only Grade 3 dermatitis (Table 4). Median weight loss during RT was 4.5 kg (range, 1.2–11.4 kg). One patient with viral load of 46,600 copies/ml experienced delayed wound healing (3-month surgical healing time) after undergoing planned neck dissection after concomitant boost RT for supraglottic carcinoma. One case of cytopenia (absolute neutrophil count, <1,000) occurred in 1 patient who received concurrent CRT and the third cycle of chemotherapy was not given. No other hematologic toxicities were observed.
Table 4. RTOG common toxicity criteria and total numbers of patients affected
| Toxicity | Grade 1 | Grade 2 | Grade 3 | Grade 4 |
|---|---|---|---|---|
| Mucositis | 0 | 3 | 6 | 0 |
| Dermatitis | 2 | 2 | 4 | 1 |
| Esophagitits | 1 | 0 | 0 | 0 |
| Xerostomia | 4 | 4 | 0 | 0 |
| Anorexia | 3 | 0 | 0 | 0 |
| Nausea | 2 | 1 | 0 | 0 |
| Fatigue | 1 | 1 | 1 | 0 |
Of the 12 patients with SCC, 10 were alive (83%) and 8 were alive without disease (66%) at a median follow up of 22 months. One patient died with no evidence of disease, and 1 patient died with recurrent disease in the neck, but the cause of death was adrenal insufficiency unrelated to the cancer or treatment. Patients alive with disease include 1 patient with persistent disease after RT and 1 who experienced local recurrence at 12 months. Late Grade 1 esophageal toxicity (dysphagia) was reported in 2 patients (both received CRT for oropharynx carcinoma), and 1 Grade 3 esophageal stricture occurred in a patient treated with CRT for larynx carcinoma.
Discussion
Individuals who are HIV positive have posed a challenge to oncologists, particularly when high-dose RT and/or chemotherapy are indicated. Numerous, albeit small, reports on management of anal and cervical cancer in this population have described relatively higher morbidity than in HIV-negative patients when aggressive regimens are used 9, 10. Patients who are HIV positive and have head and neck cancer could similarly encounter higher morbidity, as the skin and oral mucosa typically receive doses greater than 60 Gy. In this dose range, 40% to 60% experience Grade 3 to 4 mucositis when AFRT or CRT is used in HIV-negative patients (6).
Reports on head and neck irradiation in HIV-positive patients are scarce; most include a combination of patients with KS or parotid hyperplasia and few if any with SCC. To our knowledge, only 3 patients with head and neck squamous cell carcinoma have been reported to date (8). Optimal management in this population is therefore undefined. The role of RT, however, will probably increase, as epidemiologic studies have suggested an association between oral squamous cell carcinoma and HIV infection (11). Cancer registry data from 11 regions in the United States found an association between HIV and risk of developing lip cancer (relative risk, 3.1; 95% confidence interval [CI], 1.9–4.8) (12), and a similar study from Australia found the incidence of lip cancer 5.94 times higher than the standard incidence rate (95% CI, 1.92–13.8) (13). Demopoulos et al. reported that HIV-positive individuals who developed any cancer were, on average, more than a decade younger than noninfected individuals (11). These data suggest that the incidence of oral carcinoma in aging HIV-positive individuals will increase as systemic disease is controlled with HAART.
Although surgery is the mainstay of treatment in oral cavity carcinoma, adverse pathologic features such as positive lymph nodes or close margins of excision indicate the need for adjuvant RT or CRT (14). In addition, organ preservation therapy with altered fractionation RT or CRT has become increasingly accepted as primary treatment in locally advanced tumors of the larynx and pharynx 15, 16.
Our series is the first, to our knowledge, that has focused on HIV-positive patients with head and neck cancer, with 12 of 13 patients treated for SCC. Treatment regimens with regard to dose and technique were not modified because of HIV status. The median RT dose was 66.4 Gy; of the patients, 6 received concurrent chemotherapy and 1 received intensified fractionation (concomitant boost). Given the heterogeneity in tumor locations and treatments in our series, a precise comparison of toxicity with HIV-negative individuals is difficult. However, overall we observed Grade 3 to 4 adverse events in nine of 13 patients (69%), which is similar to the 77% Grade 3 to 4 overall incidence in HIV-negative patients who received CRT postoperatively, reported by Cooper et al. (17). Six patients (46%) experienced Grade 3 mucositis, which was effectively managed with oral hygiene regimens and pain medication, not unlike HIV-negative individuals receiving comparable therapy (6). In a review of acute toxicity of head and neck RT, Trotti et al. reported an 80% overall incidence of mucositis and a 43% and 57% rate of Grade 3 to 4 mucositis when CRT and AFRT were used, respectively (18). Mean weight loss from the same review ranged from 3 to 6.7 kg, depending on the study, which is similar to our observation of a mean weight loss of 4.5 kg and range of 1.8 to 11.4 kg.
Cutaneous toxicity has also been significant in HIV-positive individuals undergoing RT for anal carcinoma. Edelman and Johnstone, in a series of patients treated with concurrent CRT, reported Grade 3 to 4 skin toxicity in 8 of 17 patients, with 3 of these patients having Grade 4 reactions (19). Other authors have reported similar results with high-grade cutaneous toxicity rates of 44% to 78% 20, 21, 22, 23, 24. Given similar techniques in head-and-neck RT with beam energies of 4 to 6 MV, one would expect this to be a prevalent side effect. We observed Grade 3 to 4 cutaneous toxicity in 5 of 13 patients (38%), and only 1 patient had Grade 4 dermatitis (confluent moist desquamation), which occurred at the completion of treatment, thus not causing an interruption in RT. This patient was being treated for recurrent skin carcinoma of the face with 9-MeV electrons with a 1-cm bolus; this toxicity was not completely unexpected, given the clinical situation. The use of IMRT may decrease the incidence of desquamation, since beams are unopposed. In six cases treated with IMRT, only 1 case of Grade 3 dermatitis was observed, and this patient did not receive chemotherapy. However, no patient treated with 3D-CRT required interruption for skin toxicity either. Our series is not large enough to enable us to draw any conclusions on the superiority of one technique over another.
Perhaps the most important observation was that no toxicity-related RT interruptions were needed. One patient missed 7 days of treatment because of noncompliance and non–treatment-related toxicity. Although adverse effects have an impact on quality of life, patients generally accept more toxicity if the chance for cure is increased, as described by List et al. in a quality-of-life study (25). However, if greater toxicity results in treatment interruption, any therapeutic gain from intensified treatment could be lost, as decreased tumor control from treatment breaks is well documented 26, 27. Although it may be premature to report late toxicity at this interval, only three late toxicites (23%) were reported, with one Grade 3 (8%) esophageal stricture. This compares favorably with the 17% and 21% rate of severe late effects reported by Cooper et al. in patients who received RT or CRT, respectively (17).
Conclusion
In summary, HIV-positive individuals appear to tolerate treatment for head-and-neck cancer with toxicity similar to that in HIV-negative individuals. With adequate nutritional support and oral hygiene, treatment interruptions can be avoided. Although further study is needed to confirm these findings, we currently do not modify treatment on the basis of HIV status in patients with head-and-neck cancer.
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Note—An online CME test for this article can be taken at http://asro.astro.org under Continuing Education.
Conflict of interest: none.
PII: S0360-3016(09)02935-6
doi:10.1016/j.ijrobp.2009.06.087
© 2010 Elsevier Inc. All rights reserved.
Volume 77, Issue 5 , Pages 1375-1379, 1 August 2010
