G. Shenouda

p16 Protein Expression and Human Papillomavirus Status As Prognostic Biomarkers of Nonoropharyngeal Head and Neck Squamous Cell Carcinoma

PURPOSE Although p16 protein expression, a surrogate marker of oncogenic human papillomavirus (HPV) infection, is recognized as a prognostic marker in oropharyngeal squamous cell carcinoma (OPSCC), its prevalence and significance have not been well established in cancer of the oral cavity, hypopharynx, or larynx, collectively referred as non-OPSCC, where HPV infection is less common than in the oropharynx. PATIENTS AND METHODS p16 expression and high-risk HPV status in non-OPSCCs from RTOG 0129, 0234, and 0522 studies were determined by immunohistochemistry (IHC) and in situ hybridization (ISH). Hazard ratios from Cox models were expressed as positive or negative, stratified by trial, and adjusted for clinical characteristics. RESULTS p16 expression was positive in 14.1% (12 of 85), 24.2% (23 of 95), and 19.0% (27 of 142) and HPV ISH was positive in 6.5% (six of 93), 14.6% (15 of 103), and 6.9% (seven of 101) of non-OPSCCs from RTOG 0129, 0234, and 0522 studies, respectively. Hazard ratios for p16 expression were 0.63 (95% CI, 0.42 to 0.95; P = .03) and 0.56 (95% CI, 0.35 to 0.89; P = .01) for progression-free (PFS) and overall survival (OS), respectively. Comparing OPSCC and non-OPSCC, patients with p16-positive OPSCC have better PFS and OS than patients with p16-positive non-OPSCC, but patients with p16-negative OPSCC and non-OPSCC have similar outcomes. CONCLUSION Similar to results in patients with OPSCC, patients with p16-negative non-OPSCC have worse outcomes than patients with p16-positive non-OPSCC, and HPV may also have a role in outcome in a subset of non-OPSCC. However, further development of a p16 IHC scoring system in non-OPSCC and improvement of HPV detection methods are warranted before broad application in the clinical setting.

Familial risks of squamous cell carcinoma of the head and neck: retrospective case-control study

Abstract Objective: To determine the contribution of inheritance to the incidence of squamous cell carcinoma of the head and neck. Design: Historical cohort study. First degree relatives of cases with squamous cell carcinoma of the head and neck made up the exposed cohort and first degree relatives of spouses of cases made up the comparison unexposed cohort. Setting: Ear, nose, and throat clinic in a large metropolitan teaching hospital. Subjects: 1429 first degree relatives of 242 index cases of squamous cell carcinoma of the head and neck; as controls, 934 first degree relatives of the spouses of 156 index cases. Main outcome measures: Relative risk of developing squamous cell carcinoma in first degree relatives of cases compared with risk in first degree relatives of spouses. Results: The adjusted relative risk for developing head and neck cancer if the index case had squamous cell carcinoma of the head and neck was 3.79 (95% confidence interval 1.11 to 13.0). There were no significantly increased risks associated with a family history of cancer at other sites. The adjusted relative risk for squamous cell carcinoma of the head and neck was 7.89 (1.50 to 41.6) in first degree relatives of patients with multiple primary head and neck tumours. Conclusions: These data suggest that genetic factors are important in the aetiology of head and neck cancer, in particular for patients with multiple primary cancers. Given the prolonged exposure of these subjects to carcinogens, these genetic factors may have a role in modifying carcinogen activity or in host resistance to carcinogens. Inherited factors may be important in persons with environmentally induced cancers. Key messages Tobacco and alcohol are established risk factors, but some affected persons are non-smokers and non-drinkers Genetic makeup may determine how individuals respond to carcinogens This study found a significantly increased relative risk of 3.79 for developing head and neck cancer if a first degree relative had squamous cell carcinoma of the head and neck As with other cancers, people with multiple primary cancers of the head and neck may represent a susceptibility group as the familial risks are higher

Final Results of Local-Regional Control and Late Toxicity of RTOG 9003: A Randomized Trial of Altered Fractionation Radiation for Locally Advanced Head and Neck Cancer

PURPOSE To test whether altered radiation fractionation schemes (hyperfractionation [HFX], accelerated fractionation, continuous [AFX-C], and accelerated fractionation with split [AFX-S]) improved local-regional control (LRC) rates for patients with squamous cell cancers (SCC) of the head and neck when compared with standard fractionation (SFX) of 70 Gy. METHODS AND MATERIALS Patients with stage III or IV (or stage II base of tongue) SCC (n=1076) were randomized to 4 treatment arms: (1) SFX, 70 Gy/35 daily fractions/7 weeks; (2) HFX, 81.6 Gy/68 twice-daily fractions/7 weeks; (3) AFX-S, 67.2 Gy/42 fractions/6 weeks with a 2-week rest after 38.4 Gy; and (4) AFX-C, 72 Gy/42 fractions/6 weeks. The 3 experimental arms were to be compared with SFX. RESULTS With patients censored for LRC at 5 years, only the comparison of HFX with SFX was significantly different: HFX, hazard ratio (HR) 0.79 (95% confidence interval 0.62-1.00), P=.05; AFX-C, 0.82 (95% confidence interval 0.65-1.05), P=.11. With patients censored at 5 years, HFX improved overall survival (HR 0.81, P=.05). Prevalence of any grade 3, 4, or 5 toxicity at 5 years; any feeding tube use after 180 days; or feeding tube use at 1 year did not differ significantly when the experimental arms were compared with SFX. When 7-week treatments were compared with 6-week treatments, accelerated fractionation appeared to increase grade 3, 4 or 5 toxicity at 5 years (P=.06). When the worst toxicity per patient was considered by treatment only, the AFX-C arm seemed to trend worse than the SFX arm when grade 0-2 was compared with grade 3-5 toxicity (P=.09). CONCLUSIONS At 5 years, only HFX improved LRC and overall survival for patients with locally advanced SCC without increasing late toxicity.

THE USE OF HYPOFRACTIONATED INTENSITY-MODULATED IRRADIATION IN THE TREATMENT OF GLIOBLASTOMA MULTIFORME: PRELIMINARY RESULTS OF A PROSPECTIVE TRIAL

PURPOSE Despite major advances in treatment modalities, the prognosis of patients with glioblastoma multiforme (GBM) remains poor. Exploring hypofractionated regimens to replace the standard 6-week radiotherapy schedule is an attractive strategy as an attempt to prevent accelerated tumor cell repopulation. There is equally interest in dose escalation to the gross tumor volume where the majority of failures occur. We report our preliminary results using hypofractionated intensity-modulated accelerated radiotherapy regimen in the treatment of patients with GBM. METHODS AND MATERIALS Between July 1998 and December 2001, 25 patients with histologically proven diagnosis of GBM, Karnofsky performance status > or =60, and a postoperative tumor volume < or =110 cm3 were treated with a hypofractionated accelerated course of radiotherapy. The gross tumor volume (GTV) was defined as the contrast-enhancing lesion on the postoperative MRI T1-weighted images with the latter fused with computed tomography images for treatment planning. The planning target volume was defined as GTV + 1.5-cm margin. Using forward-planning intensity modulation (step-and-shoot technique), 60 Gy in 20 daily fractions of 3 Gy each were given to the GTV, whereas the planning target volume received a minimum of 40 Gy in 20 fractions of 2 Gy each at its periphery. Treatments were delivered over a 4-week period using 5 daily fractions per week. Dose was prescribed at the isocenter (ICRU point). Three beam angles were used in all of the cases. RESULTS Treatments were well tolerated. Acute toxicity was limited to increased brain edema during radiotherapy in 2 patients who were on tapering doses of corticosteroids. This was corrected by increasing the steroid dose. At a median follow-up of 8.8 months, no late toxicity was observed. One patient experienced visual loss at 9 months after completion of treatment. MRI suggested nonspecific changes to the optic chiasm. On review of the treatment plan, the total dose to the optic chiasm was confirmed to be equal to or less than 40 Gy in 20 fractions. When Radiation Therapy Oncology Group recursive partitioning analysis was used, 10 patients were class III-IV, and 15 patients were class V-VI. To date, 21 patients have had clinical and/or radiologic evidence of disease progression, and 16 patients have died. The median survival was 9.5 months (range: 2.8-22.9 months), the 1-year survival rate was 40%, and the median progression-free survival was 5.2 months (range: 1.9-12.8 months). CONCLUSION This hypofractionated accelerated irradiation schedule using forward planning (step-and-shoot) hypofractionated, intensity-modulated accelerated radiotherapy is feasible and seems to be a safe treatment for patients with GBM. A 2-week reduction in the treatment time may be of valuable benefit for this group of patients. However, despite this accelerated regimen, no survival advantage has been observed.

Occult Cervical Metastases: Immunoperoxidase Analysis of the Pathologically Negative Neck:

OBJECTIVES: The purpose of this study is to better estimate the true incidence of occult regional metastases associated with stage I and II squamous cell carcinoma of the oral cavity. The clinical and prognostic significance of micrometastatic disease discovered by cytokeratin immunoperoxidase reactivity in the previously pathologically N0 neck is also evaluated. METHODS: Forty patients treated between 1985 and 1996 with T1 or T2 squamous cell carcinoma of the lip and oral cavity were studied. All had primary surgical treatment including functional neck dissection. No metastases were demonstrated on hematoxylin and eosin microscopy. All specimens were reexamined with immunoperoxidase staining for cytokeratin. RESULTS: Five percent of patients had micrometastatic disease. Retrospective analysis of patients with a minimum follow-up of 2 years has failed to show a statistically significant association between a positive cytokeratin analysis and poor locoregional control or overall survival. CONCLUSIONS: Results suggest that the true incidence of occult metastases with carcinoma of the oral cavity is significantly higher than previously documented. However, the prognostic significance of these findings remains unclear.

Accelerated hypofractionated intensity-modulated radiotherapy with concurrent and adjuvant temozolomide for patients with glioblastoma multiforme: a safety and efficacy analysis.

PURPOSE Despite multimodality treatments, the outcome of patients with glioblastoma multiforme remains poor. In an attempt to improve results, we have begun a program of accelerated hypofractionated intensity-modulated radiotherapy (hypo-IMRT) with concomitant and adjuvant temozolomide (TMZ). METHODS AND MATERIALS Between March 2004 and June 2006, 35 unselected patients with glioblastoma multiforme were treated with hypo-IMRT. During a 4-week period, using a concomitant boost technique, a dose of 60 Gy and 40 Gy were delivered in 20 fractions prescribed to the periphery of the gross tumor volume and planning target volume, respectively. TMZ was administered according to the regimen of Stupp et al. RESULTS The median follow-up was 12.6 months. Of the 35 patients, 29 (82.8%) completed the combined modality treatment, and 25 (71.4%) received a median of four cycles of adjuvant TMZ. The median overall survival was 14.4 months, and the median disease-free survival was 7.7 months. The median survival time differed significantly between patients who underwent biopsy and those who underwent partial or total resection (7.1 vs. 16.1 months, p = 0.035). The median survival was also significantly different between patients with methylated vs. unmethylated 0-6-methylguanine-DNA methyltransferase promoters (14.4 vs. 8.7 months, p = 0.049). The pattern of failure was predominantly central, within 2 cm of the initial gross tumor volume. Grade 3-4 toxicity was limited to 1 patient with nausea and emesis during adjuvant TMZ administration. CONCLUSION The results of our study have shown that hypo-IMRT with concomitant and adjuvant TMZ is well tolerated with a useful 2-week shortening of radiotherapy. Despite a high number of patients with poor prognostic features (74.3% recursive partitioning analysis class V or VI), the median survival was comparable to that after standard radiotherapy fractionation schedules plus TMZ.

Sarcomatoid carcinoma of the head and neck

BACKGROUND Sarcomatoid carcinoma (SC) of the upper aerodigestive tract is a rare malignancy of which the diagnosis, optimum treatment, and prognosis remain controversial. A series of 17 patients with SC is presented, along with an analysis of potential prognostic factors, outcome following treatment, and patterns of failure. MATERIALS AND METHODS Hospital charts and pathology material were reviewed in all cases. The end points chosen were overall survival (OS), disease-free survival, and local control above the clavicles. RESULTS There were 15 male and 2 female patients with a median age of 70 years. With a median follow-up length of 29 months, the median survival time was 32 months with an actuarial survival of 72% and 42% at 2 and 5 years, respectively. CONCLUSION All recurrences were detected within 30 months from diagnosis. There was an OS advantage for patients with early-stage disease, patients with extralaryngeal presentations, and patients treated with surgery.

Hypofractionated Radiotherapy for Favorable Risk Prostate Cancer

PURPOSE Since the recognition that prostate cancer probably has a low alpha/beta ratio, hypofractionated radiotherapy has become an attractive treatment option for localized prostate cancer. However, there is little experience with the use of hypofractionation delivering a high biologically equivalent dose. We report our experience with high-dose hypofractionated radiotherapy. MATERIAL AND METHODS A total of 129 patients with favorable risk prostate cancer were treated with three-dimensional conformal radiotherapy treatment plans to the dose of 66 Gy in 22 fractions, prescribed at the isocenter. Planning target volume consisted of the prostate plus a uniform 7-mm margin, including the rectal margin. No patient received hormonal therapy. Toxicity was prospectively graded by the Common Toxicity Criteria version 3. Biochemical relapse was defined as postradiotherapy nadir prostate-specific antigen + 2 ng/mL. RESULTS With a median follow-up of 51 months, the 5-year actuarial biochemical control rate is 98%. The only 3 cases with biochemical failure did not have a clinical local relapse. More than 50% of patients did not develop acute toxicity. For late toxicity, the worst crude rate of Grade >or=2 genitourinary (GU) and gastrointestinal (GI) toxicity seen at any time during follow-up were 32% and 25%, respectively. There was no Grade 4 or 5 toxicity. At the last follow-up, persistent Grade >or=2 late GU and GI toxicity were 2% and 1.5%, respectively. CONCLUSIONS This hypofractionated regimen provides excellent biochemical control in favorable risk prostate cancer with an acceptable rate of late toxicity. Further studies exploring this hypofractionation regimen are warranted.

Energy modulated electron therapy using a few leaf electron collimator in combination with IMRT and 3D-CRT: Monte Carlo-based planning and dosimetric evaluation.

Energy modulated electron therapy (EMET) based on Monte Carlo dose calculation is a promising technique that enhances the treatment planning and delivery of superficially located tumors. This study investigated the application of EMET using a novel few-leaf electron collimator (FLEC) in head and neck and breast sites in comparison with three-dimensional conventional radiation therapy (3D-CRT) and intensity modulated radiation therapy (IMRT) techniques. Treatment planning was performed for two parotid cases and one breast case. Four plans were compared for each case: 3D-CRT, IMRT, 3D-CRT in conjunction with EMET (EMET-CRT), and IMRT in conjunction with EMET (EMET-IMRT), all of which were performed and calculated with Monte Carlo techniques. For all patients, dose volume histograms (DVHs) were obtained for all organs of interest and the DVHs were used as a means of comparing the plans. Homogeneity and conformity of dose distributions were calculated, as well as a sparing index that compares the effect of the low isodose lines. In addition, the whole-body dose equivalent (WBDE) was estimated for each plan. Adding EMET delivered with the FLEC to 3D-CRT improves sparing of normal tissues. For the two head and neck cases, the mean dose to the contralateral parotid and brain stem was reduced relative to IMRT by 43% and 84%, and by 57% and 71%, respectively. Improved normal tissue sparing was quantified as an increase in sparing index of 47% and 30% for the head and neck and the breast cases, respectively. Adding EMET to either 3D-CRT or IMRT results in preservation of target conformity and dose homogeneity. When adding EMET to the treatment plan, the WBDE was reduced by between 6% and 19% for 3D-CRT and by between 21% and 33% for IMRT, while WBDE for EMET-CRT was reduced by up to 72% when compared with IMRT. FLEC offers a practical means of delivering modulated electron therapy. Although adding EMET delivered using the FLEC results in perturbation of target conformity when compared to IMRT, it significantly improves normal tissue sparing while offering enhanced target conformity to the 3D-CRT planning. The addition of EMET systematically leads to a reduction in WBDE especially when compared with IMRT.

The potential uses of high-dose-rate brachytherapy in patients with head and neck cancer

Brachytherapy has proven to be an extremely valuable method of treatment for head and neck cancer. The data supporting its application, however, is based on continuous low-dose-rate brachytherapy. To benefit from improved radiation protection, outpatient treatments, and increased patient tolerance of treatment set-up over that encountered in conventional low-dose-rate manually afterloaded brachytherapy, we implemented a high-dose-rate remote afterloading approach in selected patients with head and neck cancers. This treatment was utilized in two different roles in managing 29 patients. In its first role, it was used as the sole treatment in 13 patients with T1–2 NO malignancies. A total of ten treatments of 450–500 cGy each were delivered twice a day with a minimum of 5–6 h between treatments. With a median follow-up of 9 months, only 1 patient failed locally. In a second role, brachytherapy was applied in a post-operative adjuvant setting following wide local excision of tumors in patients who presented with recurrent disease (12 cases) or a second primary in the head and neck (4 cases). All patients had previously received external irradiation to the head and neck. Due to this previous course of irradiation, only eight treatments of 300 cGy each were delivered, for a total of 2400 cGy over a period of 4 days. However, with a follow-up of 2–16 months, only 3 patients remain disease-free.