Completion surgery after chemoradiotherapy for cervical cancer - is there a role? UK Cancer Centre experience of hysterectomy post chemo-radiotherapy treatment for cervical cancer.

The standard treatment for locally advanced cervical cancer is chemo-radiotherapy. The presence of the residual disease after treatment is directly related to the relapse risk and to poor survival. There is a lack of consensus on the role of a subsequent surgery due to morbidity concerns. Oncological and peri-operative outcomes of completion surgery for cervical cancer were reviewed by retrospective descriptive analysis of the eligible cases between March 2012 and March 2016. Fifteen women were identified. Ten (66.7%) had a residual tumour on their post-treatment MRI. Surgical histology indicated a residual cancer in 26.7%. There were three distant recurrences. Bowel and urinary complications were most commonly reported. Offering surgery to women with a residual cervical tumour found on MRI after chemo-radiation is beneficial, despite clear risks from the dual-modality treatment. A less radical surgery is preferable. An MRI has a reasonable negative predictive value, but this study has highlighted the need to further examine the role of MRI in predicting the residual disease and recurrence. Impact statement What is already known on this subject? The standard treatment for locally advanced cervical cancer is chemo-radiotherapy. The presence of residual disease after treatment is directly related to the relapse risk and poor survival. There is a lack of consensus on the role of a subsequent surgery due to morbidity concerns. The current evidence in the UK is limited, but across the world it appears that surgery can be beneficial for patients with incomplete chemo-radiotherapy, for certain histological subtypes of cervical cancer or for bulky residual disease. What do the results of this study add? The mode of surgery is more debateable, and this study concludes that both the laparoscopic and open surgeries are acceptable, but that radical surgery should be avoided as this contributes to a significant post-operative morbidity. This study explores the role of MRI imaging in predicting the residual disease and cervical cancer recurrence, concluding that a negative MRI post-chemoradiotherapy has a good negative predictive value for squamous cell cervical cancer, but otherwise can be unreliable. What are the implications of these findings for clinical practice and/or further research? An additional explored role of the MRI in predicting a recurrence in a larger cohort will be required, and it is likely that an additional assessment with PET-CT scanning will improve specificity.

Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial.

BACKGROUND: The incidence of human papillomavirus (HPV)-positive oropharyngeal cancer, a disease affecting younger patients, is rapidly increasing. Cetuximab, an epidermal growth factor receptor inhibitor, has been proposed for treatment de-escalation in this setting to reduce the toxicity of standard cisplatin treatment, but no randomised evidence exists for the efficacy of this strategy. METHODS: We did an open-label randomised controlled phase 3 trial at 32 head and neck treatment centres in Ireland, the Netherlands, and the UK, in patients aged 18 years or older with HPV-positive low-risk oropharyngeal cancer (non-smokers or lifetime smokers with a smoking history of <10 pack-years). Eligible patients were randomly assigned (1:1) to receive, in addition to radiotherapy (70 Gy in 35 fractions), either intravenous cisplatin (100 mg/m2 on days 1, 22, and 43 of radiotherapy) or intravenous cetuximab (400 mg/m2 loading dose followed by seven weekly infusions of 250 mg/m2). The primary outcome was overall severe (grade 3-5) toxicity events at 24 months from the end of treatment. The primary outcome was assessed by intention-to-treat and per-protocol analyses. This trial is registered with the ISRCTN registry, number ISRCTN33522080. FINDINGS: Between Nov 12, 2012, and Oct 1, 2016, 334 patients were recruited (166 in the cisplatin group and 168 in the cetuximab group). Overall (acute and late) severe (grade 3-5) toxicity did not differ significantly between treatment groups at 24 months (mean number of events per patient 4·8 [95% CI 4·2-5·4] with cisplatin vs 4·8 [4·2-5·4] with cetuximab; p=0·98). At 24 months, overall all-grade toxicity did not differ significantly either (mean number of events per patient 29·2 [95% CI 27·3-31·0] with cisplatin vs 30·1 [28·3-31·9] with cetuximab; p=0·49). However, there was a significant difference between cisplatin and cetuximab in 2-year overall survival (97·5% vs 89·4%, hazard ratio 5·0 [95% CI 1·7-14·7]; p=0·001) and 2-year recurrence (6·0% vs 16·1%, 3·4 [1·6-7·2]; p=0·0007). INTERPRETATION: Compared with the standard cisplatin regimen, cetuximab showed no benefit in terms of reduced toxicity, but instead showed significant detriment in terms of tumour control. Cisplatin and radiotherapy should be used as the standard of care for HPV-positive low-risk patients who are able to tolerate cisplatin. FUNDING: Cancer Research UK.

PET-CT Surveillance versus Neck Dissection in Advanced Head and Neck Cancer.

BACKGROUND: The role of image-guided surveillance as compared with planned neck dissection in the treatment of patients with squamous-cell carcinoma of the head and neck who have advanced nodal disease (stage N2 or N3) and who have received chemoradiotherapy for primary treatment is a matter of debate. METHODS: In this prospective, randomized, controlled trial, we assessed the noninferiority of positron-emission tomography-computed tomography (PET-CT)-guided surveillance (performed 12 weeks after the end of chemoradiotherapy, with neck dissection performed only if PET-CT showed an incomplete or equivocal response) to planned neck dissection in patients with stage N2 or N3 disease. The primary end point was overall survival. RESULTS: From 2007 through 2012, we recruited 564 patients (282 patients in the planned-surgery group and 282 patients in the surveillance group) from 37 centers in the United Kingdom. Among these patients, 17% had nodal stage N2a disease and 61% had stage N2b disease. A total of 84% of the patients had oropharyngeal cancer, and 75% had tumor specimens that stained positive for the p16 protein, an indicator that human papillomavirus had a role in the causation of the cancer. The median follow-up was 36 months. PET-CT-guided surveillance resulted in fewer neck dissections than did planned dissection surgery (54 vs. 221); rates of surgical complications were similar in the two groups (42% and 38%, respectively). The 2-year overall survival rate was 84.9% (95% confidence interval [CI], 80.7 to 89.1) in the surveillance group and 81.5% (95% CI, 76.9 to 86.3) in the planned-surgery group. The hazard ratio for death slightly favored PET-CT-guided surveillance and indicated noninferiority (upper boundary of the 95% CI for the hazard ratio, <1.50; P=0.004). There was no significant difference between the groups with respect to p16 expression. Quality of life was similar in the two groups. PET-CT-guided surveillance, as compared with neck dissection, resulted in savings of £1,492 (approximately $2,190 in U.S. dollars) per person over the duration of the trial. CONCLUSIONS: Survival was similar among patients who underwent PET-CT-guided surveillance and those who underwent planned neck dissection, but surveillance resulted in considerably fewer operations and it was more cost-effective. (Funded by the National Institute for Health Research Health Technology Assessment Programme and Cancer Research UK; PET-NECK Current Controlled Trials number, ISRCTN13735240.).

Geographic variation in human papillomavirus-related oropharyngeal cancer: Data from 4 multinational randomized trials.

BACKGROUND: There are variations in the proportions of head and neck cancers caused by the human papillomavirus (HPV) between countries and regions. It is unclear if these are true variations or due to different study designs and assays. METHODS: We tested formalin-fixed paraffin-embedded diagnostic biopsies for p16 immunohistochemistry and HPV-DNA (by polymerase chain reaction [PCR] and in situ hybridization [ISH]) using validated protocols on samples from 801 patients with head and neck cancer recruited prospectively between 2006 and 2011 in 4 randomized controlled trials (RCTs). RESULTS: Twenty-one percent of patients (170 of 801) showed both HPV-DNA and p16-positivity, detected almost exclusively in oropharyngeal cancer (55%; 15 of 302); and only 1% of the patients (5 of 499) with nonoropharyngeal cancer were HPV positive. HPV-positive oropharyngeal cancer differed between Western and Eastern Europe (37%, 155 of 422 vs 6%, 8 of 144; p < .0001) and between Western Europe and Asia (37% vs 2%; 4 of 217; p < .0001). Other independent determinants of HPV positivity were tumor site and smoking. CONCLUSION: This is the first study to establish geographic variability as an independent risk factor in HPV-positive oropharyngeal cancer prevalence, with higher prevalence in Western Europe. © 2016 The Authors Head & Neck Published by Wiley Periodicals, Inc. Head Neck 38: E1863-E1869, 2016.

Brachytherapy in endometrial cancer: quantification of air gaps around a vaginal cylinder.

PURPOSE: Vaginal vault brachytherapy, prescribed to 0.5 cm, is used in endometrial cancer postoperatively to reduce the risk of vault recurrence. However, it is unknown if the vaginal mucosa is closely opposed to the vaginal cylinder, or if air gaps lift the mucosa from the cylinder. The aim of this study was to quantify the extent, magnitude, and effect on dose of any air gaps around the vaginal cylinder using CT-scan images. METHODS AND MATERIALS: Twenty-five patients treated between January and December 2005 were included in the study. The brachytherapy was prescribed to 0.5 cm with a reference volume length (RVL) of 4 cm. Pelvic CT scans taken before the first treatment with cylinder in situ were examined for presence of air gaps around the cylinder within the RVL. RESULTS: The median number of air gaps was 1 (range, 0-5) with a mean average area of 0.20 cm2 (range, 0.02-1.65). This resulted in an average of 0.86% (range, 0-6.3) of the vaginal surface within the RVL being raised from the surface of the cylinder. Over the air gaps, the dose the mucosa received at 0.5 cm was on average 86.7% (range, 54.7-97.3) of that which it would have received if there was no air gap. Overall, the dose at 0.5 cm of the whole vaginal mucosa within the RVL was 99.6% (range, 100-96.0) of that prescribed. CONCLUSIONS: Most postoperative patients with endometrial cancer do not have any clinically significant air gaps around the vaginal cylinder used to administer brachytherapy to the vaginal vault.

Sigmoid colon is an unexpected organ at risk in brachytherapy for cervix cancer.

PURPOSE: To identify organs at risk (OAR) and analyze the dose volume histograms (DVHs) for intracavitary brachytherapy in cancer of the cervix. Late toxicities are our concern in treatment of cancer cervix especially as it is presenting in younger age population. MATERIAL AND METHODS: Patients with cancer of the cervix were treated using CT and MRI compatible, high dose rate, (HDR) applicators. CT images were acquired with the intra-uterine tube and colpostats in place and subsequently imported into Varian Brachyvision planning software. We identified the gross tumour volume (GTV) and organs at risk (OARs) and analyzed the dose distribution using dose volume histograms (DVHs). Doses were calculated according to ICRU 38. Critical tissue DVHs were analysed following the American Brachytherapy Society rules. Dose points are recorded as the dose encompassed by the greatest contiguous 1 cm3, 2 cm3, and 5 cm3 volumes in the plan. RESULTS: We found the sigmoid colon to be a relatively immobile structure that repeatedly received doses in excess of 70% of the intended point A dose. The only solution in order to bring sigmoid DVHs within 5% toxicity limits was to reduce the dose to point A. Planning images and DVHs for the OARs are shown as an example of our work. CONCLUSION: The recto-sigmoid colon is identified as an unexpected OAR in a majority of cervix brachytherapy plans. A new consensus on the DVH limit of this structure will be needed in the era of CT planned brachytherapy, if arbitrary dose reductions to point A are to be the solution to the problem of sigmoid DVHs that exceed conventional tolerance limits.

Spinal cord doses in palliative lung radiotherapy schedules.

AIM: We aim to check the safety of the standard palliative radiotherapy techniques by using the Linear quadratic model for a careful estimation of the doses received by the spinal cord, in all standard palliative lung radiotherapy fields and fractionation. MATERIAL AND METHODS: All patients surveyed at this prospective audit were treated with palliative chest radiotherapy for lung cancer over a period from January to June 2005 by different clinical oncology specialists within the department. Radiotherapy field criteria were recorded and compared with the recommended limits of the MRC trial protocols for the dose and fractionation prescribed. Doses delivered to structures off the field central axis were estimated using a standard CT scan of the chest. Dose estimates were made using an SLPLAN planning system. As unexpected spinal cord toxicity has been reported after hypofractionated chest radiotherapy, a sagittal view was used to calculate the isodoses along the length of the spinal cord that could lie within the RT field. Equivalent dose estimates are made using the Linear- Quadratic Equivalent Dose formula (LQED). The relative radiation sensitivity of spinal cord for myelopathy (the a/b dose) cord has been estimated as a/b = 1 Gy. RESULTS: 17 Gy in 2 fraction and 39 Gy in 13 fraction protocols have spinal cord equivalent doses (using the linear-quadratic model) that lie within the conventional safe limits of 50 Gy in 25 fractions for the 100% isodose. However when the dosimetry is modelled for a 6 MV 100 cm isocentric linnac in 3 dimensions, and altered separations and air space inhomogeneity are considered, the D-Max doses consistently fall above this limit on our 3 model patients. CONCLUSION: The 17 Gy in 2 fraction and 39 Gy in 13 fraction protocol would risk spinal cord damage if the radiotherapist was unaware of the potential spinal cord doses. Alterative doses are suggested below 15.5 Gy/ 2 fractions (7 days apart) would be most acceptable.