A preoperative nomogram to predict the risk of synchronous distant metastases at diagnosis of primary breast cancer

Background:

The detection of synchronous metastases at primary diagnosis of breast cancer (BC) affects its initial management. A risk calculator that incorporates many factors to evaluate an individual''s risk of harbouring synchronous metastases would be useful to adapt cancer management.

Patients and Methods:

Patients with primary diagnosis of BC were identified from three institutional databases sharing homogeneous work-up recommendations. A risk score for synchronous metastases was estimated and a nomogram was constructed using the first database. Its performance was assessed by receiver characteristic (ROC) analysis. The nomogram was externally validated in the two independent cohorts.

Results:

A preoperative nomogram based on the clinical tumour size (P<0.001), clinical nodal status (P<0.001), oestrogen (P=0.17) and progesterone receptors (P=0.04) was developed. The nomogram accuracy was 87.3% (95% confidence interval (CI), 84.45–90.2%). Overall, the area under the ROC curve (AUC) was 86.1% for the validation set from the Institut Curie-René Huguenin, and 63.8% for the MD Anderson validation set. The negative predictive value (NPV) was high in the three cohorts (97–99%).

Conclusions:

We developed and validated a strong metastasis risk calculator that can evaluate with high accuracy an individual''s risk of harbouring synchronous metastases at diagnosis of primary BC.

Condensed abstract:

A nomogram to predict synchronous metastases at diagnosis of breast cancer was developed and externally validated. This tool allows avoiding unnecessary expensive work-up.     

Accuracy of a nomogram for prediction of lymph-node metastasis detected with conventional histopathology and ultrastaging in endometrial cancer

Background:

We developed a nomogram based on five clinical and pathological characteristics to predict lymph-node (LN) metastasis with a high concordance probability in endometrial cancer. Sentinel LN (SLN) biopsy has been suggested as a compromise between systematic lymphadenectomy and no dissection in patients with low-risk endometrial cancer.

Methods:

Patients with stage I–II endometrial cancer had pelvic SLN and systematic pelvic-node dissection. All LNs were histopathologically examined, and the SLNs were examined by immunohistochemistry. We compared the accuracy of the nomogram at predicting LN detected with conventional histopathology (macrometastasis) and ultrastaging procedure using SLN (micrometastasis).

Results:

Thirty-eight of the 187 patients (20%) had pelvic LN metastases, 20 had macrometastases and 18 had micrometastases. For the prediction of macrometastases, the nomogram showed good discrimination, with an area under the receiver operating characteristic curve (AUC) of 0.76, and was well calibrated (average error =2.1%). For the prediction of micro- and macrometastases, the nomogram showed poorer discrimination, with an AUC of 0.67, and was less well calibrated (average error =10.9%).

Conclusion:

Our nomogram is accurate at predicting LN macrometastases but less accurate at predicting micrometastases. Our results suggest that micrometastases are an ‘intermediate state'' between disease-free LN and macrometastasis.     

Validation of the prognostic relevance of plasma C-reactive protein levels in soft-tissue sarcoma patients

Background:

The concept of the involvement of systemic inflammation in cancer progression and metastases has gained attraction within the past decade. C-reactive protein (CRP), a non-specific blood-based marker of the systemic inflammatory response, has been associated with decreased survival in several cancer types. The aim of the present study was to validate the prognostic value of pre-operative plasma CRP levels on clinical outcome in a large cohort of soft-tissue sarcoma (STS) patients.

Methods:

Three hundred and four STS patients, operated between 1998 and 2010, were retrospectively evaluated. CRP levels and the impact on cancer-specific survival (CSS), disease-free survival (DFS) and overall survival (OS) were assessed using Kaplan–Meier curves and univariate as well as multivariate Cox proportional models. Additionally, we developed a nomogram by supplementing the plasma CRP level to the well-established Kattan nomogram and evaluated the improvement of predictive accuracy of this novel nomogram by applying calibration and Harrell''s concordance index (c-index).

Results:

An elevated plasma CRP level was significantly associated with established prognostic factors, including age, tumour grade, size and depth (P<0.05). In multivariate analysis, increased CRP levels were significantly associated with a poor outcome for CSS (HR=2.05; 95% CI=1.13–3.74; P=0.019) and DFS (HR=1.88; 95% CI=1.07–3.34; P=0.029). The estimated c-index was 0.74 using the original Kattan nomogram and 0.77 when the plasma CRP level was added.

Conclusion:

An elevated pre-operative CRP level represents an independent prognostic factor that predicts poor prognosis and improves the predictive ability of the Kattan nomogram in STS patients. Our data suggest to further prospectively validate its potential utility for individual risk stratification and clinical management of STS patients.     

Prognostic role of EGFR gene copy number and KRAS mutation in patients with locally advanced rectal cancer treated with preoperative chemoradiotherapy

Background:

Epidermal growth factor receptor (EGFR), evaluated by immunohistochemistry, has been shown to have prognostic significance in patients with colorectal cancer. Gene copy number (GCN) of EGFR and KRAS status predict response and outcome in patients treated with anti-EGFR therapy, but their prognostic significance in colorectal cancer patients is still unclear.

Methods:

We have retrospectively reviewed the baseline EGFR GCN, KRAS status and clinical outcome of 146 locally advanced rectal cancer (LARC) patients treated with preoperative chemoradiotherapy. Pathological response evaluated by Dworak''s tumour regression grade (TRG), disease-free survival (DFS) and overall survival (OS) were analysed.

Results:

Tumour regression grade 4 and TRG3–4 were achieved in 14.4 and 30.8% of the patients respectively. Twenty-nine (19.9%) and 33 patients (19.2%) had an EGFR/nuclei ratio >2.9 and CEP7 polisomy >50% respectively; 28 patients (19.2%) had a KRAS mutation. Neither EGFR GCN nor KRAS status was statistically correlated to TRG. 5-year DFS and OS were 63.3 and 71.5%, respectively, and no significant relation with EGFR GCN or KRAS status was found.

Conclusion:

Our data show that EGFR GCN and KRAS status are not prognostic factors in LARC treated with preoperative chemoradiation.     

Population-based comparison of prognostic factors in invasive micropapillary and invasive ductal carcinoma of the breast

Background:

Invasive micropapillary carcinoma (IMPC) is a variant of breast carcinoma with a higher propensity for lymph node metastases compared with invasive ductal carcinoma (IDC).

Methods:

Retrospective analysis of 636 IMPC and 297 735 IDC cases in the Surveillance, Epidemiology and End Results database comparing disease-specific survival (DSS) and overall survival (OS) between IMPC and IDC.

Results:

A higher percentage of IMPC cases (52.0%) had nodal metastases compared with IDC cases (34.6%). The 5-year DSS and OS for IMPC was 91.8% and 82.9%, respectively compared with 88.6% and 80.5% for IDC, respectively. For both IMPC and IDC, oestrogen-receptor positivity was associated with better survival, while having four or more positive lymph nodes or larger tumour size correlated with worse survival. Radiotherapy provided a survival benefit for both histological types.

Conclusions:

Despite IMPC''s higher propensity for lymph node metastasis, IMPC has DSS and OS that compare favourably with IDC.     

Lymph node density in oral cavity cancer: results of the International Consortium for Outcomes Research

Background:

Lymph node density (LND) has previously been reported to reliably predict recurrence risk and survival in oral cavity squamous cell carcinoma (OSCC). This multicenter international study was designed to validate the concept of LND in OSCC.

Methods:

The study included 4254 patients diagnosed as having OSCC. The median follow-up was 41 months. Five-year overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), locoregional control and distant metastasis rates were calculated using the Kaplan–Meier method. Lymph node density (number of positive lymph nodes/total number of excised lymph nodes) was subjected to multivariate analysis.

Results:

The OS was 49% for patients with LND⩽0.07 compared with 35% for patients with LND>0.07 (P<0.001). Similarly, the DSS was 60% for patients with LND⩽0.07 compared with 41% for those with LND>0.07 (P<0.001). Lymph node density reliably stratified patients according to their risk of failure within the individual N subgroups (P=0.03). A modified TNM staging system based on LND ratio was consistently superior to the traditional system in estimating survival measures.

Conclusion:

This multi-institutional study validates the reliability and applicability of LND as a predictor of outcomes in OSCC. Lymph node density can potentially assist in identifying patients with poor outcomes and therefore for whom more aggressive adjuvant treatment is needed.     

External validation of an online nomogram in patients undergoing radical nephroureterectomy for upper urinary tract urothelial carcinoma

Background:

The objective was to validate an online nomogram developed based on the French collaborative national database on upper urinary tract urothelial carcinoma (UUT-UC) using a different cohort.

Methods:

The study comprised 328 patients with UUT-UC who underwent radical nephroureterectomy. The discrimination of models was quantified using Harrell''s concordance index. The relationship between the model-derived and actuarial cancer-specific mortality was graphically explored within calibration plots. Calibration was also assessed using the quartiles of the predicted survival at 3 and 5 years and calculation of the corresponding observed Kaplan–Meier estimates. Clinical net benefit was evaluated constructing decision curve analysis.

Results:

The discrimination accuracy of the nomograms at 3 and 5 years was 71.6% and 71.8%, respectively. Although nomograms discriminated well by Kaplan–Meier curves, and log-rank tests were all highly significant, the calibration plots tended to exaggerate the overestimation of mortality between predicted and observed probabilities at 3 and 5 years for survival. When compared with the AJCC/UICC staging system, the nomograms performed well across a wide range of threshold probabilities using decision curve analysis.

Conclusion:

The online nomogram is a highly accurate prognostic tool for patients with UUT-UC treated with radical nephroureterectomy. The model can provide an accurate estimate of the individual risk of cancer-specific mortality. Further improvement and implementation of novel molecular marker is needed.     

Health behaviour advice to cancer patients: the perspective of social network members

Background:

Survival for many cancers is improved by healthier lifestyles, but giving lifestyle advice to cancer patients may seem insensitive. We investigated attitudes of members of cancer patients'' social networks towards doctors giving lifestyle advice.

Methods:

We identified social network members through a population survey of UK adults (n=2024, age ⩾50) by asking respondents whether anyone close to them had ever had cancer (n=1273). Individuals with a cancer diagnosis themselves (n=222) were termed cancer survivors. Attitudes towards doctors giving advice to cancer patients on physical activity, diet and weight were each assessed with eight items.

Results:

Most social network members (88–93%) and survivors (87–93%) agreed that advice on diet, activity and weight would be ‘beneficial'', ‘helpful'' and ‘encouraging'', and 84–87% thought it was ‘the doctor''s duty'' to provide it. Few network members (10–18%) or survivors (10–24%) believed it was ‘unnecessary'', ‘interfering'', ‘insensitive'' or implied ‘blame''. Adjusted analyses using composite scores showed that attitudes did not differ between the groups.

Conclusion:

Few cancer survivors or members of social networks of individuals with cancer thought lifestyle advice would be insensitive, and most thought it would be beneficial. These results help counter doubts about the acceptability of lifestyle advice in the cancer context.     

External multicentre validation of a nomogram predicting the risk of relapse in patients with borderline ovarian tumours

Background:

The Obermair nomogram was recently developed to predict the risk of relapse in patients with borderline ovarian tumours (BOTs) based on five readily available clinical, biological, and pathological characteristics. We set out to externally validate and assess its robustness using a multi-institutional BOT database.

Methods:

All consecutive patients treated for BOTs in the two participating centres between January 1980 and December 2008 and who had all the nomogram variables documented were identified for analysis.

Results:

Three hundred and fourteen eligible patients were identified and used for external validation analysis. The median follow-up and initial relapse time were 46.43 (range: 0.1–360) and 66.64 (range: 8–77) months, respectively. The nomogram concordance index was 0.54 (95% CI, 0.52–0.56). The correspondence between the actual relapse and the nomogram predictions suggests a limited calibration of the nomogram in the validation cohort.

Conclusion:

This external validation study of the Obermair nomogram showed limitations in its generalisability to a new and independent patient population.     

Preoperative nomogram for the identification of lymph node metastasis in early cervical cancer

Background:

The objective of this study is to construct a preoperative nomogram predicting lymph node metastasis (LNM) in early-cervical cancer patients.

Methods:

Between 2009 and 2012, 493 early-cervical cancer patients received hysterectomy and pelvic/para-aortic lymphadenectomy. Patients who were diagnosed during 2009–2010 were assigned to a model-development cohort (n=304) and the others were assigned to a validation cohort (n=189). A multivariate logistic model was created from preoperative clinicopathologic data, from which a nomogram was developed and validated. A predicted probability of LNM<5% was defined as low risk.

Results:

Age, tumour size assessed by magnetic resonance imaging, and LNM assessed by positron emission tomography/computed tomography were independent predictors of nodal metastasis. The nomogram incorporating these three predictors demonstrated good discrimination and calibration (concordance index=0.878; 95% confidence interval (CI), 0.833−0.917). In the validation cohort, the discrimination accuracy was 0.825 (95% CI, 0.736−0.895). In the model-development cohort, 34% of them were classified as low risk and negative predictive value (NPV) was 99.0%. In the validation cohort, 38% were identified as low risk and NPV was 95.8%. Integrating the model-development and validation cohorts, negative likelihood ratio was 0.094 (95% CI, 0.036−0.248).

Conclusion:

A robust nomogram predicting LNM in early cervical cancer was developed. This model may improve clinical trial design and help physicians to decide whether lymphadenectomy should be performed.     

ALDH1 is an independent prognostic factor for patients with stages II–III rectal cancer after receiving radiochemotherapy

Background:

About one in five patients with locally advanced rectal cancer (RC) suffers recurrence or distant metastasis after neoadjuvant therapy. We investigated how cancer stem cell markers change after neoadjuvant therapy and how these markers relate to recurrence.

Methods:

Pretreatment biopsies and postoperative specimens were taken from 64 patients with locally advanced rectal adenocarcinoma who received preoperative radiochemotherapy (RCT) between sampling. Samples were tested immunohistochemically for CD44, LGR5, ALDH1 and CD166; scores were dichotomised as high or low. The median follow-up period was 36 months.

Results:

High expression of CD44, LGR5, ALDH and CD166 was found in 38%, 5%, 48% and 10%, respectively, before RCT and 86%, 33%, 71% and 52%, respectively, after RCT. CD44 (P=0.001), LGR5 (P=0.049) and CD166 (P=0.003) were significantly upregulated after RCT. Whereas no recurrence was seen during the follow-up in the low ALDH group, 40% of the high ALDH group suffered recurrence. In multivariate COX analysis, postoperative ALDH1 independently predicted poor prognosis in patients with RC who received RCT (P=0.0095).

Conclusion:

Preoperative RCT upregulates expression of stem cell markers in patients with RC. High post-treatment ALDH1 expression predicts poor prognosis for these patients after neoadjuvant therapy.     

An external validation study of nomograms designed to predict isolated loco-regional and distant endometrial cancer recurrences: how applicable are they?

Background:

To externally validate and assess the robustness of two nomograms to predict the recurrence risk of women with endometrial cancer (EC).

Methods:

Using an independent, multicentre external patient cohort we assessed the discrimination and calibration of two nomograms – the 3-year isolated loco-regional (ILRR) and distant (DR) recurrence nomograms – in women with surgically treated stage I–III EC.

Results:

Two hundred and seventy one eligible women were identified from two university hospital databases and the Senti-Endo trial. The median follow-up and initial recurrence time were 38.1 (range: 12–69) and 22.0 (range: 8.3–55) months, respectively. The overall recurrence rate was 13.8% (37 out of 271). Predictive accuracy according to the discrimination was 0.69 (95% CI, 0.58–0.79) and 0.66 (95% CI, 0.60–0.71) for the 3-year ILRR and DR nomograms, respectively. The correspondence between observed recurrence rate and the nomogram predictions suggests a moderate calibration of the nomograms in the validation cohort.

Conclusion:

The nomograms were externally validated and shown to be partly generalisable to a new and independent patient population. The tools need to be improved by including information on the lymph node status and adjuvant therapies.     

Clinico-pathological nomogram for predicting BRAF mutational status of metastatic colorectal cancer

Background:

In metastatic colorectal cancer (mCRC), BRAFV600E mutation has been variously associated to specific clinico-pathological features.

Methods:

Two large retrospective series of mCRC patients from two Italian Institutions were used as training-set (TS) and validation-set (VS) for developing a nomogram predictive of BRAFV600E status. The model was internally and externally validated.

Results:

In the TS, data from 596 mCRC patients were gathered (RAS wild-type (wt) 281 (47.1%); BRAFV600E mutated 54 (9.1%)); RAS and BRAFV600E mutations were mutually exclusive. In the RAS-wt population, right-sided primary (odds ratio (OR): 7.80, 95% confidence interval (CI) 3.05–19.92), female gender (OR: 2.90, 95% CI 1.14–7.37) and mucinous histology (OR: 4.95, 95% CI 1.90–12.90) were independent predictors of BRAFV600E mutation, with high replication at internal validation (100%, 93% and 98%, respectively). A predictive nomogram was calculated: patients with the highest score (right-sided primary, female and mucinous) had a 81% chance to bear a BRAFV600E-mutant tumour; accuracy measures: AUC=0.812, SE:0.034, sensitivity:81.2% specificity:72.1%. In the VS (508 pts, RAS wt: 262 (51.6%), BRAFV600E mutated: 49 (9.6%)), right-sided primary, female gender and mucinous histology were confirmed as independent predictors of BRAFV600E mutation with high accuracy.

Conclusions:

Three simple and easy-to-collect characteristics define a useful nomogram for predicting BRAF status in mCRC with high specificity and sensitivity.     

Vaginal self-sampling is a cost-effective way to increase participation in a cervical cancer screening programme: a randomised trial

Background:

Cervical cancer screening coverage remains insufficient in most countries. Our objective was to assess whether in-home vaginal self-sampling with a dry swab for high-risk human papillomavirus (HR-HPV) testing is effective and cost-effective in increasing participation in cervical cancer screening.

Methods:

In March 2012, 6000 unscreened women aged 30–65 years, living in a French region covered by a screening programme, who had not responded to an initial invitation to have a Pap smear were equally randomised to three groups: ‘no intervention'' ‘recall'', women received a letter to have a Pap smear; and ‘self-sampling'', women received a self-sampling kit to return to a centralised virology laboratory for PCR-based HPV testing.

Results:

Participation was higher in the ‘self-sampling'' than in the ‘no intervention'' group (22.5% vs 9.9%, P<0.0001; OR 2.64) and ‘recall'' group (11.7%, P<0.0001; OR 2.20). In the ‘self-sampling'' group, 320 used the self-sampling kit; for 44 of these women with positive HR-HPV test results, 40 had the recommended triage Pap smear. The ICER per extra screened woman was 77.8€ and 63.2€ for the ‘recall'' and ‘self-sampling'' groups, respectively, relative to the ‘no intervention'' group.

Conclusions:

Offering an in-home, return-mail kit for vaginal self-sampling with a dry swab is more effective and cost-effective than a recall letter in increasing participation in cervical cancer screening.     

Multidisciplinary decisions in breast cancer: does the patient receive what the team has recommended?

Background:

A multidisciplinary team (MDT) approach to breast cancer management is the gold standard. The aim is to evaluate MDT decision making in a modern breast unit.

Methods:

All referrals to the breast MDT where breast cancer was diagnosed from 1 July 2009 to 30 June 2011 were included. Multidisciplinary team decisions were compared with subsequent patient management and classified as concordant or discordant.

Results:

Over the study period, there were 3230 MDT decisions relating to 705 patients. Overall, 91.5% (2956 out of 3230) of decisions were concordant, 4.5% (146 out of 3230), were discordant and 4% (128 out of 3230) had no MDT decision. Of 146 discordant decisions, 26 (17.8%) were considered ‘unjustifiable'' as there was no additional information available after the MDT to account for the change in management. The remaining 120 discordant MDT decisions were considered ‘justifiable'', as management was altered due to patient choice (n=61), additional information available after MDT (n=54) or MDT error (n=5).

Conclusion:

The vast majority of MDT decisions are implemented. Management alteration was most often due to patient choice or additional information available after the MDT. A minority of management alterations were ‘unjustifiable'' and the authors recommend that any patient whose treatment is subsequently changed should have MDT rediscussion prior to treatment.     

Uptake of tamoxifen in consecutive premenopausal women under surveillance in a high-risk breast cancer clinic

Background:

Randomised trials of tamoxifen versus placebo indicate that tamoxifen reduces breast cancer risk by approximately 33%, yet uptake is low. Approximately 10% of women in our clinic entered the IBIS-I prevention trial. We assess the uptake of tamoxifen in a consecutive series of premenopausal women not in a trial and explore the reasons for uptake through interviews.

Methods:

All eligible women between 33 and 46 years at ⩾17% lifetime risk of breast cancer and undergoing annual mammography in our service were invited to take a 5-year course of tamoxifen. Reasons for accepting (n=15) or declining (n=15) were explored using semi-structured interviews.

Results:

Of 1279 eligible women, 136 (10.6%) decided to take tamoxifen. Women >40 years (74 out of 553 (13.4%)) and those at higher non-BRCA-associated risk were more likely to accept tamoxifen (129 out of 1109 (11.6%)). Interviews highlighted four themes surrounding decision making: perceived impact of side effects, the impact of others'' experience on beliefs about tamoxifen, tamoxifen as a ‘cancer drug'', and daily reminder of cancer risk.

Conclusions:

Tamoxifen uptake was similar to previously ascertained uptake in a randomised controlled trial (IBIS-I). Concerns were similar in women who did or did not accept tamoxifen. Decision making appeared to be embedded in the experience of significant others.     

Time-dependent risk of developing distant metastasis in breast cancer patients according to treatment,age and tumour characteristics

Background:

Metastatic breast cancer is a severe condition without curative treatment. How relative and absolute risk of distant metastasis varies over time since diagnosis, as a function of treatment, age and tumour characteristics, has not been studied in detail.

Methods:

A total of 9514 women under the age of 75 when diagnosed with breast cancer in Stockholm and Gotland regions during 1990–2006 were followed up for metastasis (mean follow-up=5.7 years). Time-dependent development of distant metastasis was analysed using flexible parametric survival models and presented as hazard ratio (HR) and cumulative risk.

Results:

A total of 995 (10.4%) patients developed distant metastasis; the most common sites were skeleton (32.5%) and multiple sites (28.3%). Women younger than 50 years at diagnosis, with lymph node-positive, oestrogen receptor (ER)-negative, >20 mm tumours and treated only locally, had the highest risk of distant metastasis (0–5 years'' cumulative risk =0.55; 95% confidence interval (CI): 0.47–0.64). Women older than 50 years at diagnosis, with ER-positive, lymph node-negative and ⩽20-mm tumours, had the same and lowest cumulative risk of developing metastasis 0–5 and 5–10 years (cumulative risk=0.03; 95% CI: 0.02–0.04). In the period of 5–10 years after diagnosis, women with ER-positive, lymph node-positive and >20-mm tumours were at highest risk of distant recurrence. Women with ER-negative tumours showed a decline in risk during this period.

Conclusion:

Our data show no support for discontinuation at 5 years of clinical follow-up in breast cancer patients and suggest further investigation on differential clinical follow-up for different subgroups of patients.     

Correlation of BRAF and NRAS mutation status with outcome,site of distant metastasis and response to chemotherapy in metastatic melanoma

Background:

The prognostic significance of BRAF and NRAS mutations in metastatic melanoma patients remains uncertain, with several studies reporting conflicting results, often biased by the inclusion of patients treated with BRAF and MEK (MAPK) inhibitors. We therefore interrogated a historical cohort of patients free of the confounding influence of MAPK inhibitor therapy.

Methods:

Patients with available archival tissue first diagnosed with metastatic melanoma between 2002 and 2006 were analysed. Mutational analysis was performed using the OncoCarta Panel. Patient characteristics, treatment outcome and survival were correlated with BRAF/NRAS mutation status.

Results:

In 193 patients, 92 (48%) melanomas were BRAF-mutant, 39 (20%) were NRAS-mutant and 62 (32%) were wild-type for BRAF/NRAS mutations (wt). There was no difference in response to chemotherapy based on mutation status (35–37%). The distant disease-free interval (DDFI) was significantly shorter in patients with wt melanoma (27.9 months vs 35.1 for BRAF and 49.1 for NRAS) although this was not significant in multivariate analysis. Survival from stage IV melanoma diagnosis was not significantly different based on mutation status. The DDFI was significantly shorter in patients with BRAF^V600K/R versus BRAF^V600E melanoma in univariate and multivariate analyses.

Conclusions:

BRAF and NRAS mutation status does not influence survival in metastatic melanoma.     

Detection of HPV-associated oropharyngeal tumours in a 16-year cohort: more than meets the eye

Background:

Accurate assessment of the prevalence of the human papilloma virus (HPV) in oropharyngeal tumours (OpSCC) is important because HPV-positive OpSCC are consistently associated with an improved overall survival. Recently, an algorithm has become available that reliably detects clinically relevant HPV in tumour tissue, however, no complete cohorts have been tested. The aim was to determine the prevalence of active high-risk HPV infection in a complete cohort of OpSCC collected over a 16-year period.

Methods:

Using a triple algorithm of p16 immunohistochemistry, HPV-BRISH and HPV-PCR, we assessed the prevalence of active HPV infection in all OpSCC diagnosed in our hospital from 1997 to 2012 (n=193) and a random selection of 200 oral tumours (OSCC).

Results:

Forty-seven OpSCC (24%) were HPVGP PCR-positive; 42 cases were HPV16+, 1 HPV18+, 3 HPV33+ and 1 HPV35+. Brightfield in situ hybridisation did not identify additional HPV-positive cases. Human papilloma virus-associated tumour proportion increased from 13% (1997–2004) to 30% (2005–2012). Human papilloma virus-positivity was an independent predictor for longer disease-specific survival (HR=0.22; 95%CI:0.10–0.47). Only one OSCC was HPV+.

Conclusions:

In our cohort, the incidence of HPV-associated OpSCC is low but increasing rapidly. The strict detection algorithm, analysis of disease-specific survival and the complete cohort, including palliatively treated patients, may influence the reported prevalence and prognostic value of HPV in OpSCC.     

Phase II trial of docetaxel,cisplatin and 5FU chemotherapy in locally advanced and metastatic penis cancer (CRUK/09/001)

Background:

Penis cancer is rare and clinical trial evidence on which to base treatment decisions is limited. Case reports suggest that the combination of docetaxel, cisplatin and 5-flurouracil (TPF) is highly active in this disease.

Methods:

Twenty-nine patients with locally advanced or metastatic squamous carcinoma of the penis were recruited into a single-arm phase II trial from nine UK centres. Up to three cycles of chemotherapy were received (docetaxel 75 mg m⁻² day 1, cisplatin 60 mg m⁻² day 1, 5-flurouracil 750 mg m⁻² per day days 1–5, repeated every 3 weeks). Primary outcome was objective response (assessed by RECIST). Fourteen or more responses in 26 evaluable patients were required to confirm a response rate of 60% or higher (Fleming-A''Hern design), warranting further evaluation. Secondary endpoints included toxicity and survival.

Results:

10/26 evaluable patients (38.5%, 95% CI: 20.2–59.4) achieved an objective response. Two patients with locally advanced disease achieved radiological complete remission. 65.5% of patients experienced at least one grade 3/4 adverse event.

Conclusion:

Docetaxel, cisplatin and 5FU did not reach the pre-determined threshold for further research and caused significant toxicity. Our results do not support the routine use of TPF. The observed complete responses support further investigation of combination chemotherapy in the neoadjuvant setting.