Prognostic impact of retropharyngeal lymphadenopathy in early-stage HPV-associated oropharyngeal cancer: Implications for staging optimization.

OBJECTIVES: We analyzed the prognostic impact of retropharyngeal lymphadenopathy (RPL) in stage I node-positive HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). MATERIALS AND METHODS: We performed a centralized and blinded radiographic review of the pre-treatment images of 234 consecutive patients with AJCC 8th edition stage I cT1-2N1 HPV-associated OPSCC treated with definitive chemoradiation from 2006 to 2016. Five-year disease control and survival outcomes were reported. The prognostic significance of RPL was evaluated through multivariable analysis adjusting for age, smoking history (<10 vs. >10 pack-years), and systemic regimen received. RESULTS: Median follow-up for surviving patients was 49 months (range: 16-121). RPL was associated with increased locoregional recurrence (LRR) (17.0% v. 3.4%, p = 0.01) and distant metastasis (DM) (29.1% v. 5.9%, p = 0.001) and inferior progression-free survival (PFS) (55.6% v. 88.2%, p < 0.001) and overall survival (OS) (60.6% v. 91.2%, p < 0.001). In stage I patients who did not receive high-dose cisplatin (HDC), RPL was associated with worse LRR (p = 0.04), DM (p = 0.03), PFS (p < 0.001), and OS (p < 0.001), whereas in those who did receive HDC, RPL was only associated with increased DM (p = 0.002) and inferior PFS (p = 0.04). CONCLUSION: This study suggests that RPL portends a poor prognosis in stage I node-positive HPV-associated OPSCC. The negative impact on LRR may have been mitigated by receipt of HDC. Outcomes of stage I disease with RPL were comparable to historical reports of patients with more advanced-stage disease. Incorporation of RPL into future disease staging should be considered in order to optimize risk-stratification and exclude unsuitable candidates from treatment de-intensification efforts.

Triweekly carboplatin as a potential de-intensification agent in concurrent chemoradiation for early-stage HPV-associated oropharyngeal cancer.

OBJECTIVE: We compared high-dose cisplatin (HDC) vs. triweekly carboplatin (TC)-based chemoradiation in patients with HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). MATERIALS AND METHODS: A retrospective review was conducted from 2006 to 2015 of 421 patients with locally advanced p16-positive OPSCC receiving definitive radiotherapy concurrent with 3 cycles of HDC (100 mg/m2, n = 230) or TC (AUC = 5, n = 191). Three-year locoregional recurrence (LRR), distant metastasis (DM), overall recurrence rate (ORR), overall survival (OS), and cause-specific survival (CSS) are reported. HDC and TC were compared accounting for age, sex, comorbidity index score, smoking history, T stage, and N stage. RESULTS: For all-comers, no difference was observed between HDC and TC for any outcome except for ORR which was lower in patients receiving HDC (12% vs. 17%, p = 0.03). On stage-based analysis, no difference was observed between agents for any outcome for stage I or II disease. However, patients with stage III disease receiving HDC had lower rates of LRR (9% vs. 21%, p = 0.03), DM (7% vs. 28%, p = 0.006), and ORR (14% vs. 40%, p = 0.002), and superior OS (89% vs. 78%, p = 0.04) and CSS (95% vs. 80%, p = 0.02). Patients receiving HDC experienced higher rates of grade 3 leukopenia (25% vs. 11%, p < 0.001), weight loss ≥20% from baseline (21% vs. 8%, p < 0.001), and gastrostomy-tube placements (66% vs. 27%, p < 0.001). CONCLUSION: TC demonstrated comparable outcomes to HDC for stage I or II HPV-associated OPSCC but was inferior to HDC for stage III disease. TC was associated with less toxicity and may be a potential de-intensification agent for early-stage disease.

Impact of chemotherapy regimen on treatment outcomes in patients with HPV-associated oropharyngeal cancer with T4 disease treated with definitive concurrent chemoradiation.

OBJECTIVES: Although human papilloma virus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is typically associated with a good prognosis, patients with T4 disease experience relatively high rates of treatment failure. Our aim was to identify predictors of relapse among patients with clinical T4 disease. MATERIAL & METHODS: A retrospective review was conducted of 93 consecutive patients who underwent definitive concurrent chemoradiation for HPV-associated OPSCC with clinical T4 disease from July 2006 to December 2015. Three-year outcomes, including locoregional recurrence (LRR), distant metastasis (DM), overall survival (OS), and cancer-specific survival (CSS), were examined and reported from the date of treatment completion. Multivariable analysis using a Cox proportional hazards model was performed to test associations between outcome and patient and disease characteristics as well as chemotherapy regimen (high-dose cisplatin (HDC) vs. other). RESULTS: Median follow-up for surviving patients was 50 months (range 18-133). For all-comers, 3-year rates of LRR, DM, OS, and CSS were 15%, 19%, 79%, and 86%, respectively. On multivariable analysis, the only factor prognostic for patient outcomes was the chemotherapy regimen. For patients who received HDC vs. an alternative regimen, 3-year LRR, DM, OS, and CSS, were 9% vs. 20% (p = 0.09), 10% vs. 28% (p = 0.04), 89% vs. 67% (p = 0.04), and 96% vs. 77% (p = 0.02), respectively. CONCLUSION: In patients with HPV-associated OPSCC bearing clinical T4 disease, receipt of a concurrent systemic agent other than HDC resulted in increased treatment failure and inferior survival. This analysis suggests that HDC should remain the preferred concurrent regimen for these patients.

Statin therapy is not associated with prostate cancer recurrence among patients who underwent radiation therapy.

We investigated whether statin use is associated with reduced risk of recurrence in prostate cancer patients who undergo radiotherapy. A retrospective cohort of 774 patients from a California health plan was followed for 5 years. Statin use prior to, during and after radiotherapy was not associated with prostate cancer recurrence [hazard ratio=0.99 (0.70-1.39), 0.87 (0.62-1.22) and 0.78 (0.55-1.09), respectively] in multivariable Cox models. No clear dose-response relationship was observed for average daily statin dose or duration of statin use. Our findings do not support a preventive benefit of statins in prostate cancer recurrence after radiotherapy.

Prognostic significance of histology and positive lymph node involvement following radical hysterectomy in carcinoma of the cervix.

OBJECTIVE: Lymph node (LN) metastasis portends a poor outcome in women with carcinoma of the uterine cervix. We queried a large database to analyze the importance of number of positive LN and histology in relation to survival after radical hysterectomy and lymphadenectomy. METHODS: Data were collected from the Surveillance, Epidemiology, and End Results Program on women who had primary surgery for the years 1988 to 2003 (n = 4559). Statistical analyses were performed using conventional methods. RESULTS: The median number of LNs examined per patient has significantly declined in recent years (P = 0.003). The 5-year rates of cause specific and overall survival were 94% and 91%, 76% and 69%, 62% and 58%, and 41% and 35%, for 0, 1 to 2, 3 to 9 and > or =10 positive LNs, respectively. Pathologic LN involvement was associated with higher grade, higher stage, larger tumor size, and squamous cell histology. Predictors for both cause specific and overall survival on multivariate analysis included number of involved LN, histology, tumor grade, tumor size, disease stage, and pelvis or paraaortic lymphatic involvement. CONCLUSIONS: Adenocarcinoma histology independently predicted for a more aggressive phenotype, particularly in women with LN involvement. The number of LNs examined did not independently predict for survival when adjusted for patient and disease characteristics, providing context for the investigation of sentinel node biopsy or other sampling methods. LN positive disease in carcinoma of the cervix predicts a prognosis that is inversely related to the number of involved nodes. Tumor grade, size, and FIGO stage were associated with increasing risk for lymph node metastases.

Surgery and radiotherapy improves survival in patients with anaplastic thyroid carcinoma: analysis of the surveillance, epidemiology, and end results 1983-2002.

OBJECTIVES: Anaplastic thyroid carcinoma is associated with a high rate of local recurrence and poor prognosis. This analysis examines the effects of surgery and radiotherapy on survival. METHODS AND MATERIALS: Anaplastic thyroid carcinoma patients from the Surveillance, Epidemiology, and End Results database from 1983 to 2002 with > or = 1-month survival after diagnosis who either had surgery performed or recommended were included in the analysis. RESULTS: Two hundred sixty-one patients met the inclusion criteria for analysis. Median survival was 4 months. Distant or metastatic disease, tumor size >7 cm, and treatment with surgery plus or minus radiotherapy were statistically significant as prognostic for survival on multivariate analysis (P < 0.05). When stratified by extent of disease, the addition of radiotherapy to surgery resulted in improved survival for patients with disease extending into adjacent tissue (P = 0.05); however, patients who had disease confined to the capsule or had further extension or distant metastatic disease did not benefit from radiotherapy after surgery (P > 0.05). CONCLUSIONS: Surgery and radiotherapy improves survival in patients with anaplastic thyroid carcinoma. Aggressive treatment with surgery and chemoradiation should be encouraged.

Incidence, mortality, and prognostic factors of small cell carcinoma of the cervix.

OBJECTIVE: To compare the incidence, mortality, and presentation of small cell carcinoma of the cervix with other histologies. METHODS: From 1977 to 2003, 290 women with small cell carcinoma of the cervix uteri were identified from the Surveillance, Epidemiology, and End Results database. Also, 27,527 patients with squamous cell carcinoma of the cervix and 5,231 patients with adenocarcinoma of the cervix were identified for comparison. The annual incidence was calculated and examined for trend. Patient and disease characteristics were compared among histologies. Univariable analyses were conducted using the log-rank test. Multivariable analysis was performed using Cox regression. RESULTS: The mean annual incidence for small cell carcinoma was 0.06 per 100,000 women, compared with 6.6 and 1.2 for squamous cell carcinoma and adenocarcinoma, respectively. There were significant differences at presentation between small cell carcinoma compared with squamous cell carcinoma and adenocarcinoma for race, treatment, International Federation of Gynecology and Obstetrics stage, and lymph node involvement (P<.05). A trend for improved survival was identified for adenocarcinoma (P=.036) and squamous cell carcinoma (P<.001) but not for small cell carcinoma (P=.672). Five-year survival for small cell carcinoma (35.7%) was worse compared with squamous cell carcinoma (60.5%, hazard ratio 0.55; 95% confidence interval (CI) 0.43-0.69) and adenocarcinoma (69.7%, hazard ratio 0.48; 95% CI 0.37-0.61). On multivariable analysis, age, stage, and race were prognostic for survival in women with small cell carcinoma (P<.05). CONCLUSION: Small cell carcinoma is a rare histology of cervical cancer associated with a worse prognosis and a predilection for nodal and distant metastasis. The decrease in survival was marked in early-stage and node-negative patients. Because of the high rates of nodal involvement even with early-stage disease, multimodality treatment with radiotherapy and chemotherapy should be considered. LEVEL OF EVIDENCE: II.

Comparison of cervical esophagus dose-volumes for three radiotherapy techniques for head and neck cancer.

PURPOSE: This study compares the radiation dose-volume of the cervical esophagus during head and neck radiotherapy using three different techniques. METHODS: Treatment plans of 58 patients from 3/04 to 1/06 treated with bilateral head and neck radiotherapy were analyzed retrospectively. A comparison of the cervical esophagus dose with three-field 3D conformal RT (3DRT, n=34), whole-field IMRT (WF-IMRT, n=12), and half-beam IMRT (HB-IMRT, n=12) was performed. The volumes of esophagus receiving > or =50Gy (V50), > or =54Gy (V54) and > or = 60Gy (V60) and lengths receiving circumferential dose > or = 50Gy (L50) and > or = 54Gy (L54) were evaluated. RESULTS: Maximum dose, V54 and L54 were greater for the first 2cm and entire cervical esophagus with WF-IMRT than HB-IMRT or 3DRT. In patients requiring a high match, WF-IMRT was associated with a greater maximum dose, V54 and L54 than HB-IMRT and 3DRT (p<0.05). In the low match group, WF-IMRT was associated with a greater V54 and L54 (p<0.05). Low neck disease, low primary site, and definitive radiotherapy were associated with increased irradiation of the esophagus. CONCLUSION: Treatment of the lower neck with IMRT is associated with increased irradiation to the cervical esophagus, and dose constraints should be included to reduce toxicity.

The risk of second primary malignancies up to three decades after the treatment of differentiated thyroid cancer.

BACKGROUND: The 10-yr survival rate of patients with differentiated thyroid cancer exceeds 90%. These patients may be at elevated risk for secondary cancers. METHODS: The risk of nonthyroid second primary malignancies after differentiated thyroid cancer was determined in 30,278 patients diagnosed between 1973 and 2002 from centers participating in the National Cancer Institute's Surveillance, Epidemiology, and End Results program. Median follow-up was 103 months (range, 2-359 months). Risk was further assessed for the addition of radioisotope therapy, gender, latency to development of secondary cancer, and age at thyroid cancer diagnosis. RESULTS: There were 2158 patients who developed a total of 2338 nonthyroid second primary malignancies, significantly more than that expected in the general population [observed/expected (O/E) = 1.09; 95% confidence interval (CI), 1.05-1.14; P < 0.05; absolute excess risk per 10,000 person-years (AER) = 6.39]. A significantly greater risk of second primary malignancies over that expected in the general population was for patients treated with radioisotopes (O/E = 1.20; 95% CI, 1.07-1.33; AER = 11.8) as well as for unirradiated patients (O/E = 1.05; 95% CI, 1.00-1.10; AER = 3.53). However, the increased risk was greater for the irradiated vs. the unirradiated cohort (relative risk = 1.16; 95% CI, 1.05-1.27; P < 0.05). Gender did not affect risk. The greatest risk of second primary cancers occurred within 5 yr of diagnosis and was elevated for younger patients. CONCLUSIONS: The overall risk of second primary malignancies is increased for thyroid cancer survivors and varies by radioisotope therapy, latency, and age at diagnosis.

Planned neck dissection after definitive radiotherapy or chemoradiation for base of tongue cancers.

OBJECTIVES: The study goal was to analyze the role of planned neck dissection for squamous cell carcinoma of the base of the tongue treated with definitive radiotherapy or chemoradiation. STUDY DESIGN, SETTING: We conducted a retrospective study of patients with squamous cell carcinoma of the base of the tongue undergoing planned neck dissection after definitive radiotherapy or chemoradiation. RESULTS: Twenty-two of 41 (53.7%) patients had one to six positive residual lymph nodes after receiving definitive radiotherapy or chemoradiation. Neck control rates were 92.3% and 88.3% at two and five years, respectively. Three of 22 (13.6%) patients with pathological residual nodal disease had regional or locoregional failures, compared with 1 of 19 (5.3%) patients with a pathologically complete response (P = 0.39). CONCLUSIONS: We observed a high incidence of pathologically residual lymph nodes after definitive radiotherapy or chemoradiation. SIGNIFICANCE: Planned neck dissection following definitive radiotherapy or chemoradiation is highly effective in achieving regional control of squamous cell carcinoma of the base of the tongue.

Intensity-modulated radiotherapy using implanted fiducial markers with daily portal imaging: assessment of prostate organ motion.

PURPOSE: To assess our single institutional experience with daily localization, using fiducials for prostate radiotherapy. METHODS AND MATERIALS: From January 2004 to September 2005, 33 patients were treated with 1,097 intensity-modulated radiation treatments, using three implanted fiducials. Daily portal images were obtained before treatments. Shifts were made for deviations > or =3 mm in the left-right (LR), superior-inferior (SI), and anterior-posterior (AP) dimensions. RESULTS: Of 1,097 treatments, 987 (90%) required shifts. Shifts were made in the LR, SI, and AP dimensions in 51%, 67%, and 58% of treatments, respectively. In the LR dimension, the median distance shifted was 5 mm. Of 739 shifts in the SI dimension, 73% were in the superior direction for a median distance of 6 mm, and 27% were shifted inferiorly for a median distance of 5 mm. The majority of shifts in the AP dimension were in the anterior direction (87%). Median distances shifted in the anterior and posterior directions were 5 mm and 4 mm, respectively. The median percentage of treatments requiring shifts per patient was 93% (range, 57-100%). Median deviations in the LR, SI, and AP dimensions were 3 mm, 4 mm, and 3 mm, respectively. Deviations in the SI and AP dimensions were more often in the superior rather than inferior (60% vs. 29%) and in the anterior rather than posterior (70% vs. 16%) directions. CONCLUSIONS: Interfraction prostate motion is significant. Daily portal imaging with implanted fiducials improves localization of the prostate, and is necessary for the reduction of treatment margins.

Treatment of oropharyngeal squamous cell carcinoma with external beam radiation combined with interstitial brachytherapy.

BACKGROUND: We reviewed the outcomes of oropharyngeal squamous cell carcinoma treated with external beam radiation and interstitial brachytherapy. METHODS: Ninety patients with squamous cell carcinoma of the oropharynx were treated with interstitial brachytherapy at the University of Utah between 1984 and 2001. Seventy-two patients received external beam radiotherapy (EBRT) followed by brachytherapy boost, 11 had surgery followed by EBRT and brachytherapy, 4 had surgery and brachytherapy, and 3 were treated with brachytherapy alone. Median doses for EBRT and brachytherapy were 50 and 24 Gy, respectively. RESULTS: Median follow-up after brachytherapy was 48.3 months for all patients. Five-year local control, disease-free survival, and overall survival were 76%, 61%, and 55%. For T1, T2, T3, and T4, 5-year local control rates were 83%, 79%, 79%, and 64%, respectively. Severe complications occurred in 13 patients, including 2 treatment-related deaths. CONCLUSIONS: EBRT combined with interstitial brachytherapy provide good local control rates for locally advanced oropharyngeal squamous cell carcinoma.

Does radiotherapy around the time of pregnancy for Hodgkin's disease modify the risk of breast cancer?

PURPOSE: To determine whether the risk of secondary breast cancer after radiotherapy (RT) for Hodgkin's disease is greater among women who underwent RT around time of pregnancy. METHODS AND MATERIALS: The records of 382 women treated with RT for Hodgkin's disease were reviewed and divided into those who received RT around the time of pregnancy and those who were not pregnant. Comparisons of the overall incidence, actuarial rates, and latency to breast cancer between the two groups were made. Multivariate Cox regression modeling was performed to determine possible contributing factors. RESULTS: Of the 382 women, 14 developed breast cancer (3.7%). The increase in the overall incidence (16.0% vs. 2.3%, p = 0.0001) and the actuarial rate of breast cancer among the women in the pregnant group (p = 0.011) was statistically significant. The women treated around the time of pregnancy had a 10- and 15-year actuarial rate of breast cancer of 6.7% and 32.6%, respectively. The 10-year and 15-year actuarial rate for the nonpregnant women was 0.4% and 1.7%, respectively. The median latency from RT to the diagnosis of breast cancer was 13.1 and 18.9 years for women in the pregnant and nonpregnant groups, respectively. In the multivariate analysis, pregnancy around the time of RT was the only variable associated with an increased risk of breast cancer. The risk was dependent on the length of time from pregnancy to RT, with women receiving RT during pregnancy and within 1 month of pregnancy having an increased risk of breast cancer compared with nonpregnant women and women irradiated later than 1 month after pregnancy (hazard ratio, 22.49; 95% confidence interval, 5.56-90.88; p <0.001). CONCLUSION: The results of this study indicate that the risk of breast cancer after RT is greater with irradiation around the time of pregnancy. This suggests that pregnancy is a time of increased sensitivity of breast tissue to the carcinogenic effects of radiation. Because of the small sample size and limited follow-up, additional studies are recommended to confirm these findings.

Increased atherosclerotic lesions in apoE mice with plasma phospholipid transfer protein overexpression.

OBJECTIVE: Plasma phospholipid transfer protein (PLTP) is involved in the metabolism of HDL and apolipoprotein B (apoB)-containing lipoproteins. Atherosclerosis susceptibility is decreased in mice with PLTP deficiency that is associated with decreased liver production of apoB-containing lipoproteins and increase in their antioxidant. To investigate additionally the effect of PLTP on the development of atherosclerosis, we overexpressed PLTP in mice. METHODS AND RESULTS: PLTP was overexpressed in apoE knockout mice using an adenovirus-associated virus (AAV)-mediated system. Plasma PLTP activity was 1.3- to 2-fold higher in mice injected with AAV-PLTP than in mice injected with control AAV-GFP, and PLTP levels were sustained during the experiment period (4 months). We show that 2-fold increased PLTP activity results in (1) a decrease in HDL cholesterol, HDL phospholipid, and apoAI levels; (2) a decrease in vitamin E contents in total plasma and in individual lipoprotein fractions; (3) an increase in lipoprotein oxidizability as assessed by copper-induced formation of conjugated dienes; (4) an increase in autoantibodies against oxidized apoB-containing particles; and (5) an increase in atherosclerosis lesions in proximal aorta. CONCLUSIONS: These observations indicate that elevated plasma PLTP levels constitute a novel, long-term risk factor for atherosclerosis.