Oncologic outcomes of de-escalating axillary treatment in clinically node-positive breast cancer patients treated with neoadjuvant systemic therapy - A two center cohort study.

BACKGROUND: The aim of the present study was to report the 5-year axillary recurrence-free interval (aRFI) in clinically node-positive breast cancer patients treated according to a de-escalating axillary treatment protocol after neoadjuvant systemic therapy (NST). METHODS: All patients diagnosed in two hospitals between October 2014 and March 2021 were identified retrospectively. Data on diagnostic workup, treatment and follow-up was collected. Adjuvant axillary treatment was considered based on the initial staging using 18F-FDG PET/CT and the results of axillary lymph node marking with a radioactive-iodine seed protocol or a targeted axillary dissection procedure. Follow-up was updated until 27th April 2024. Kaplan-Meier curves were calculated to report the 5-year aRFI with corresponding 95 % confident intervals (95%-CI). RESULTS: A total of 199 patients were included. Axillary pathological complete response was reported in 66 (33.2 %). Based on the treatment protocol and initial clinical staging, no adjuvant axillary treatment was indicated in 30 patients (15 %), while 139 (70 %) received axillary radiotherapy without performance of an axillary lymph node dissection (ALND). The remaining 30 patients (15 %) underwent an ALND with additional locoregional radiotherapy. A median follow-up of 62 months (30-106) showed that 4 (2 %) patients experienced an axillary recurrence after 7, 8, 36 and 36 months, respectively. In all 4 patients, synchronous distant metastases were diagnosed. The estimated 5-year aRFI was 97.8 % (95%-CI 95.6-99.9 %) CONCLUSION: Although longer follow-up should be awaited before final conclusions can be drawn regarding the oncological safety of this approach, the implementation of a de-escalating axillary treatment protocol appears to be safe since the estimated 5-year aRFI is 97.8 %.

Narrowing the difference in dose delivery for IOERT and IOBT for locally advanced and locally recurrent rectal cancer.

Purpose: Intra-operative radiotherapy (IORT) has been used as a tool to provide a high-dose radiation boost to a limited volume of patients with fixed tumors with a likelihood of microscopically involved resection margins, in order to improve local control. Two main techniques to deliver IORT include high-dose-rate (HDR) brachytherapy, termed 'intra-operative brachytherapy' (IOBT), and electrons, termed 'intra-operative electron radiotherapy' (IOERT), both having very different dose distributions. A recent paper described an improved local recurrence-free survival favoring IOBT over IOERT for patients with locally advanced or recurrent rectal cancer and microscopically irradical resections. Although several factors may have contributed to this result, an important difference between the two techniques was the higher surface dose delivered by IOBT. This article described an adaptation of IOERT technique to achieve a comparable surface dose as dose delivered by IOBT. Material and methods: Two steps were taken to increase the surface dose for IOERT: 1. Introducing a bolus to achieve a maximum dose on the surface, and 2. Re-normalizing to allow for the same prescribed dose at reference depth. Conclusions: We describe and propose an adaptation of IOERT technique to increase surface dose, decreasing the differences between these two techniques, with the aim of further improving local control. In addition, an alternative method of dose prescription is suggested, to consider improved comparison with other techniques in the future.

Primary hrHPV DNA testing in cervical cancer screening: how to manage screen-positive women? A POBASCAM trial substudy.

BACKGROUND: High-risk human papillomavirus (hrHPV) testing has higher sensitivity but lower specificity than cytology for cervical (pre)-cancerous lesions. Therefore, triage of hrHPV-positive women is needed in cervical cancer screening. METHODS: A cohort of 1,100 hrHPV-positive women, from a population-based screening trial (POBASCAM: n = 44,938; 29-61 years), was used to evaluate 10 triage strategies, involving testing at baseline and six months with combinations of cytology, HPV16/18 genotyping, and/or repeat hrHPV testing. Clinical endpoint was cervical intraepithelial neoplasia grade 3 or worse (CIN3(+)) detected within four years; results were adjusted for women not attending repeat testing. A triage strategy was considered acceptable, when the probability of no CIN3(+) after negative triage (negative predictive value, NPV) was at least 98%, and the CIN3(+) risk after positive triage (positive predictive value, PPV) was at least 20%. RESULTS: Triage at baseline with cytology only yielded an NPV of 94.3% [95% confidence interval (CI), 92.0-96.0] and a PPV of 39.7% (95% CI, 34.0-45.6). An increase in NPV, against a modest decrease in PPV, was obtained by triaging women with negative baseline cytology by repeat cytology (NPV 98.5% and PPV 34.0%) or by baseline HPV16/18 genotyping (NPV 98.8% and PPV 28.5%). The inclusion of both HPV16/18 genotyping at baseline and repeat cytology testing provided a high NPV (99.6%) and a moderately high PPV (25.6%). CONCLUSIONS: Triaging hrHPV-positive women by cytology at baseline and after 6 to 12 months, possibly in combination with baseline HPV16/18 genotyping, seems acceptable for cervical cancer screening. IMPACT: Implementable triage strategies are provided for primary hrHPV screening in an organized setting.

Evaluation of 14 triage strategies for HPV DNA-positive women in population-based cervical screening.

High-risk human papillomavirus (hrHPV) testing has a higher sensitivity but lower specificity than cytology for detection of high-grade intraepithelial neoplasia (CIN). To avoid over-referral to colposcopy and overtreatment, hrHPV-positive women require triage testing and/or followup. A total of 25,658 women (30-60 years) enrolled in a population-based cohort study had an adequate baseline Pap smear and hrHPV test. The end-point was cumulative two-year risk of CIN grade 3 or worse (CIN3+). In a post-hoc analysis, fourteen triage/followup strategies for hrHPV-positive women (n = 1,303) were evaluated for colposcopy referral rate, positive (PPV) and negative predictive value (NPV). Five strategies involved triage testing without a repeat test and nine strategies involved triage testing followed by one repeat testing. The tests were cytology, hrHPV, HPV16/18 genotyping and HPV16/18/31/33/45 genotyping. Results were adjusted for women in the cohort study who did not attend repeat testing. Of the strategies without repeat testing, combined cytology and HPV16/18/31/33/45 genotyping gave the highest NPV of 98.9% (95%CI 97.6-99.5%). The corresponding colposcopy referral rate was 58.1% (95%CI 55.4-60.8%). Eight of the nine strategies with retesting had an estimated NPV of at least 98%. Of those, cytology triage followed by cytology at 12 months had a markedly lower colposcopy referral rate of 33.4% (95%CI 30.2-36.7%) than the other strategies. The NPV of the latter strategy was 99.3% (95%CI 98.1-99.8%). Triage hrHPV-positive women with cytology, followed by repeat cytology testing yielded a high NPV and modest colposcopy referral rate and appear to be the most feasible management strategy.

Human papillomavirus testing for the detection of high-grade cervical intraepithelial neoplasia and cancer: final results of the POBASCAM randomised controlled trial.

BACKGROUND: Human papillomavirus (HPV) testing is more sensitive for the detection of high-grade cervical lesions than is cytology, but detection of HPV by DNA screening in two screening rounds 5 years apart has not been assessed. The aim of this study was to assess whether HPV DNA testing in the first screen decreases detection of cervical intraepithelial neoplasia (CIN) grade 3 or worse, CIN grade 2 or worse, and cervical cancer in the second screening. METHODS: In this randomised trial, women aged 29-56 years participating in the cervical screening programme in the Netherlands were randomly assigned to receive HPV DNA (GP5+/6+-PCR method) and cytology co-testing or cytology testing alone, from January, 1999, to September, 2002. Randomisation (in a 1:1 ratio) was done with computer-generated random numbers after the cervical specimen had been taken. At the second screening 5 years later, HPV DNA and cytology co-testing was done in both groups; researchers were masked to the patient's assignment. The primary endpoint was the number of CIN grade 3 or worse detected. Analysis was done by intention to screen. The trial is now finished and is registered, number ISRCTN20781131. FINDINGS: 22,420 women were randomly assigned to the intervention group and 22 518 to the control group; 19 999 in the intervention group and 20,106 in the control group were eligible for analysis at the first screen. At the second screen, 19 579 women in the intervention group and 19,731 in the control group were eligible, of whom 16,750 and 16,743, respectively, attended the second screen. In the second round, CIN grade 3 or worse was less common in the intervention group than in the control group (88 of 19 579 in the intervention group vs 122 of 19,731 in the control group; relative risk 0·73, 95% CI 0·55-0·96; p=0·023). Cervical cancer was also less common in the intervention group than in the control group (four of 19 579 in the intervention group vs 14 of 19,731; 0·29, 0·10-0·87; p=0·031). In the baseline round, detection of CIN grade 3 or worse did not differ significantly between groups (171 of 19 999 vs 150 of 20,106; 1·15, 0·92-1·43; p=0·239) but was significantly more common in women with normal cytology (34 of 19,286 vs 12 of 19,373; 2·85, 1·47-5·49; p=0·001). Furthermore, significantly more cases of CIN grade 2 or worse were detected in the intervention group than in the control group (267 of 19 999 vs 215 of 20,106; 1·25, 1·05-1·50; p=0·015). In the second screen, fewer HPV16-positive CIN grade 3 or worse were detected in the intervention group than in the control group (17 of 9481 vs 35 of 9354; 0·48, 0·27-0·85; p=0·012); detection of non-HPV16-positive CIN grade 3 or worse did not differ between groups (25 of 9481 vs 25 of 9354; 0·99, 0·57-1·72; p=1·00). The cumulative detection of CIN grade 3 or worse and CIN grade 2 or worse did not differ significantly between study arms, neither for the whole study group (CIN grade 3 or worse: 259 of 19 999 vs 272 of 20,106; 0·96, 0·81-1·14, p=0·631; CIN grade 2 or worse: 427 of 19 999 vs 399 of 20,106; 1·08, 0·94-1·24; p=0·292), nor for subgroups of women invited for the first time (CIN grade 3 or worse in women aged 29-33 years: 102 of 3139 vs 105 of 3128; 0·97, 0·74-1·27; CIN grade 2 or worse in women aged 29-33 years: 153 of 3139 vs 151 of 3128; 1·01, 0·81-1·26; CIN grade 3 or worse in women aged 34-56 years: 157 of 16,860 vs 167 of 16 978; 0·95, 0·76-1·18; CIN grade 2 or worse in women aged 34-56 years: 274 of 16,860 vs 248 of 16 978; 1·11, 0·94-1·32). INTERPRETATION: Implementation of HPV DNA testing in cervical screening leads to earlier detection of clinically relevant CIN grade 2 or worse, which when adequately treated, improves protection against CIN grade 3 or worse and cervical cancer. Early detection of high-grade cervical legions caused by HPV16 was a major component of this benefit. Our results lend support to the use of HPV DNA testing for all women aged 29 years and older. FUNDING: Zorg Onderzoek Nederland (Netherlands Organisation for Health Research and Development).

Comparison of HPV and cytology triage algorithms for women with borderline or mild dyskaryosis in population-based cervical screening (VUSA-screen study).

We studied the effectiveness of high-risk human papillomavirus (hrHPV) triage for immediate colposcopy in women with borderline or mild dyskaryosis (BMD). In the Utrecht province of the Netherlands, women aged 30-60 years who participated in the regular cervical screening programme were offered hrHPV testing and cytology (intervention group) or cytology only (control group). In the intervention group (n = 337), women with BMD were immediately referred for colposcopy only if the sample was hrHPV positive. Women with a hrHPV negative test were advised to repeat cytology at 6 and 18 months and were referred for colposcopy if and when the repeat test result was positive (BMD or worse). In the control group (n = 329), referral of women with BMD was delayed until cytology was repeatedly positive at 6 or 18 months. The CIN3 detection rates were 10.7% (36/337) in the intervention group and 6.4% (21/329) in the control group (p = 0.047). Moreover, hrHPV triaging resulted in shorter time to diagnosis (154 vs. 381 days). Although the number of colposcopy referrals was 51.5% higher in the intervention group than in the control group, the medical costs per detected CIN3 were slightly lower ([euro] 4781 vs. [euro] 6235). If, in addition, hrHPV negative women had been referred back to routine screening at baseline, the CIN3 rate would have been 10.1% (34/337) and colposcopy rate would only have been 30.4% higher than in the control group. This study shows that hrHPV triaging of women with BMD is at least as effective for detecting CIN3 as repeat cytology, also when hrHPV negative women are referred back to routine screening.

Alternating high-risk human papillomavirus infection: consequences of progression to cervical intraepithelial neoplasia.

BACKGROUND: Nearly every Dutch woman will be exposed to genital human papillomavirus (HPV) at least once during her lifetime, and most likely several times. In the current study, the authors investigated the prevalence of high-risk-HPV (HR-HPV) infection and the likelihood of progression to cervical intraepithelial neoplasia (CIN). METHODS: In this study, the course of HR-HPV infection in 703 women was observed. From a database of 720,016 negative cytology smears, the authors selected 703 women based on the availability of at least 2 HR-HPV polymerase chain reaction tests. The authors database stores not only the HPV data but also all other cytologic and histologic data, allowing the detection of women who progressed from negative cytology to CIN within a period of 10 years. RESULTS: Of the 703 selected women, 159 were found to have alternating HR-HPV infection (change from a negative HR-HPV test to a positive test or vice versa), 40 had a persistently positive HR-HPV test, and 504 women had a persistently negative HR-HPV test. The percentage of alternating HPV infection declined over time from 37% to 7%. Of the women age older than 40 years, 17% had an alternating HR-HPV infection, 2 of whom developed CIN. These findings led the authors to conclude that all the women in the current study with an increased risk of developing type 2 or 3 CIN were identified using 2 HPV tests. Women age older than 40 years still have a significant risk of acquiring a HR-HPV. CONCLUSIONS: In light of the current study findings, the authors believe it is worth considering the inclusion of women age 40 years and older who have negative cytology for HPV testing as part of the Dutch national screening program.

Dutch solutions for liquid-based cytology: analysis of unsatisfactory slides and HPV testing of equivocal cytology.

The liquid-based techniques to obtain microscopy slides for cervical screening have replaced conventional smears almost completely in the USA, but not in all European countries. The decision making process to use liquid-based cytology (LBC) for nationwide screening programs depends on the health system. In a pilot study of over 7,000 screenees, we analyzed the unsatisfactory LBC slides and tested the equivocal cytologies for HPV by using the LiPA test. For comparison over 48,000 conventional screening data were used. Compared to conventional smears, the LBC slides were highly cellular, the state of fixation was much better, and obscuring blood did not exist. The unsatisfactory rate showed an increase from 262/100,000 (conventional smears) to 357/100,000 (LBC slides) due to too thick, undiagnosable epithelial fragments on the LBC slides. HPV testing of the equivocal cytology leads to a better patient management and less unnecessary referrals.