Durvalumab versus placebo with chemoradiotherapy for locally advanced cervical cancer (CALLA): a randomised, double-blind, phase 3 trial.

BACKGROUND: Concurrent chemoradiotherapy has been the standard of care for locally advanced cervical cancer for over 20 years; however, 30-40% of treated patients have recurrence or progression within 5 years. Immune checkpoint inhibition has improved outcomes for patients with PD-L1 positive metastatic or recurrent cervical cancer. We assessed the benefit of adding durvalumab, a PD-L1 antibody, with and following chemoradiotherapy for locally advanced cervical cancer. METHODS: The CALLA randomised, double-blind, phase 3 trial included 105 hospitals across 15 countries. Patients aged at least 18 years with previously untreated locally advanced cervical cancer (adenocarcinoma, squamous, or adenosquamous; International Federation of Gynaecology and Obstetrics [FIGO] 2009 stage IB2-IIB lymph node positive, stage ≥III any lymph node status) and WHO or Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) through an interactive web response system using a permuted block size of 4 to receive durvalumab (1500 mg intravenously once every 4 weeks) or placebo with and following chemoradiotherapy, for up to 24 cycles. Chemoradiotherapy included 45 Gy external beam radiotherapy at 5 fractions per week concurrent with intravenous cisplatin (40 mg/m2) or carboplatin (area under the concentration-time curve 2) once weekly for 5 weeks, followed by image-guided brachytherapy (high-dose rate, 27·5-30 Gy or low-dose/pulse-dose rate, 35-40 Gy). Randomisation was stratified by disease stage status (FIGO stage and node status) and geographical region. Chemoradiotherapy quality was continuously reviewed. The primary endpoint was progression-free survival, assessed by the investigator using Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03830866. FINDINGS: Between Feb 15, 2019, and Dec 10, 2020, 770 women were randomly assigned (385 to durvalumab and 385 to placebo; median age 49 years [IQR 41-57]). Median follow-up was 18·5 months (IQR 13·2-21·5) in the durvalumab group and 18·4 months (13·2-23·7) in the placebo group. At data cutoff, median progression-free survival had not been reached (95% CI not reached-not reached) for either group (HR 0·84; 95% CI 0·65-1·08; p=0·17); 12-month progression-free survival was 76·0% (71·3-80·0) with durvalumab and 73·3% (68·4-77·5) with placebo. The most frequently reported grade 3-4 adverse events in both groups were anaemia (76 [20%] of 385 in the durvalumab group vs 56 [15%] of 384 in the placebo group) and decreased white blood cells (39 [10%] vs 49 [13%]). Serious adverse events occurred for 106 (28%) patients who received durvalumab and 89 (23%) patients who received placebo. There were five treatment-related deaths in the durvalumab group (one case each of urinary tract infection, blood loss anaemia, and pulmonary embolism related to chemoradiotherapy only; one case of endocrine disorder related to durvalumab only; and one case of sepsis related to both durvalumab and chemoradiotherapy). There was one treatment-related death in the placebo group (pneumonia related to chemoradiotherapy). INTERPRETATION: Durvalumab concurrent with chemoradiotherapy was well tolerated in participants with locally advanced cervical cancer, however it did not significantly improve progression-free survival in a biomarker unselected, all-comers population. Concurrent durvalumab plus chemoradiotherapy warrants further exploration in patients with high tumoral PD-L1 expression. Rigorous monitoring ensured high chemoradiotherapy compliance with advanced technology and allowed patients to receive optimal care. FUNDING: AstraZeneca.

[Fertility preservation in female cancer patients.] / Daganatos nobetegek termékenységének megorzése.

The incidence of cancer increases with age and as family planning is being delayed, there is a growing number of cancer patients whose fertility may be affected by oncological treatments. International guidelines recommend that all reproductive age cancer patients, including adolescent patients, should be referred for fertility preservation consultation, and if necessary, fertility preservation procedures should be performed. Fertility preservation enables cancer survivors to offer a chance for biological parenthood after recovery. In this review, the gonadotoxic effects of oncological therapies and the fertility preservation possibilities for female cancer patients based on international recommendations and literature are discussed. Our next review will provide detailed information on the special fertility preservation possibilities for different cancer types. The two reviews may help to elaborate a national guidance. Orv Hetil. 2023; 164(28): 1094-1101.

Online Assessment of Morphological Awareness in Grades 2-4: Its Development and Relation to Reading Comprehension.

The aims of the study are to construct an online instrument to assess different aspects of morphological awareness and to examine its development and its relation to reading comprehension in grades 2-4 in Hungarian children. Altogether, 4134 students were tested. The online test evaluated inflectional, derivational, and compound morphological skills with five subtests. The instrument proved to be reliable. CFA examinations revealed that the five subtests were empirically distinguishable dimensions. Inflectional, derivational, and compound morphology as the three main dimensions of morphological awareness were also empirically supported by our data. Morphological awareness skills improved significantly and developed in parallel with reading skills throughout grades 2-4. The increase in the development of morphological awareness from grade 2 to grade 3 tends to be faster than the growth between grade 3 and 4. Positive moderate correlations were found between morphological skills and reading comprehension and the relationships seem to be stable throughout the three grades. The most significant predictor of reading comprehension is the Affix Identification for Nonwords subtest. Our study showed that morphological awareness could be assessed efficiently through online media and drew attention to the importance of morphological awareness in the development of reading comprehension and linguistic intelligence.

[Radiotherapy and radio-chemotherapy of cervical cancer]. / A méhnyakrák sugárkezelése és radiokemoterápiája.

Radiotherapy has a significant role in the management of cervical cancer. Radiotherapy is indicated in two-thirds of all cervical cancer patients. Indications of radiotherapy are based on level I-II evidences in the vast majority of cases, although in some cases the use of radiotherapy is supported by the results of retrospective clinical trials. In this review, indications of curative and palliative irradiation and radio-chemotherapy are summarized and technological advances of contemporary external beam radiotherapy and brachytherapy are presented.

[Initial experience with image-guided and intensity-modulated postoperative radiotherapy of gynecological cancer]. / Nõgyógyászati tumorok képvezérelt, intenzitásmodulált adjuváns sugárkezelésével szerzett kezdeti tapasztalataink.

Our goal was to determine the extent of the CTV-PTV margin. Accuracy of patient setup was checked with daily CBCT. Two radiation oncologists performed the image matching independently. The CTV-PTV margin was calculated with the van Herk formula. The treatment plans were created with the Varian Eclipse v11 planning system, and the treatments were carried out with a Varian TrueBeam accelerator by using RapidArc technique with two full arcs. Dose constraints on the target volume and organs at risk recommended by international bodies were applied. Conformity number (CN) for PTV, V45 and V50 for organs at risk were used to assess and compare the treatment plans of RapidArc and 3D-KRT (conformal radiotherapy) techniques. The average CTV-PTV margins with or without IGRT were 0.67 cm vs. 1.53 cm, 0.66 cm vs. 1.25 cm and 0.34 cm vs. 0.98 cm in vertical, longitudinal and lateral directions, respectively. In case of daily on-line CBCT verification 0.5 cm margin can be used.

Pathologic complete remission after preoperative high-dose-rate brachytherapy in patients with operable cervical cancer: preliminary results of a prospective randomized multicenter study.

The role of preoperative intrauterine brachytherapy (BT) in the multidisciplinary treatment of early stage cervical carcinoma (ESCC) is controversial. In 2005, a prospective randomized multicenter study was initiated in Hungary in order to explore the potential advantages of preoperative high-dose-rate (HDR) BT. In this article we evaluate the efficiency of preoperative HDR BT by the rate of pathologic complete remission (pCR) in the first 185 patients enrolled in the study at the National Institute of Oncology and at the Uzsoki Municipal Cancer Center in collaboration with the 1st Department of Gynaecology and Obstetrics of Semmelweis University, Budapest, Hungary. In arm A, patients received 2x8Gy preoperative intracavitary HDR BT, while in arm B no preoperative treatment was given. In both arms patients underwent radical Wertheim (Piver III) hysterectomy. The pCR rate was 25.7% after preoperative HDR BT, while it was only 11.2% with surgery alone (p=0.03), in these cases the tumor was eliminated during the diagnostic excision or conisation. The rate of positive surgical margins was 1.5% after preoperative BT, while it was as high as 11.4% without preoperative RT (p=0.02). There was no significant difference in the local tumor control (LTC), distant metastases free survival (DMFS) and overall survival (OS) between the two arms. According to our preliminary results preoperative intracavitary HDR BT significantly increases the rate of pCR and decreases the rate of positive surgical margins in patients with ESCC. Longer follow-up is required to establish the possible impact of pCR on the ultimate LTC and OS.

Analysis of the full-length VP2 protein of canine parvoviruses circulating in Hungary.

In recent years, the number of cases of disease caused by canine parvovirus 2 (CPV-2) in vaccinated dogs has increased. The aim of the present study was to identify CPV-2 strains present in Hungary. Forty-two out of 50 faecal specimens examined were positive, and 25 VP2 sequences were determined and analysed. Based on the current classification, the Hungarian viruses belong to New CPV-2a type, except two viruses that are recombinants of vaccine viruses and CPV-2a strains. The Tyr324Ile alteration was detected for the first time in Europe, and a "Hungarian-specific" substitution (Ala516Thr) was also identified in this study. The immunologically important parts of the currently spreading canine parvoviruses were examined and found to differ greatly from the vaccine strains that are widely used in Hungary.

[Complete pathologic remission after preoperative high-dose brachytherapy in patients with operable cervical cancer: preliminary results of a prospective randomized study]. / Patológiai komplett remisszió preoperatív, nagy dózisteljesítményû brachyterápiát követoen operábilis méhnyakdaganatos betegeknél: egy prospektív, randomizált vizsgálat elozetes eredményei.

The purpose of the study was a preliminary evaluation of the efficacy of preoperative intracavitary high-dose-rate brachytherapy (HDR BT) in sterilization of the specimen of operable cervical cancer patients enrolled into a prospective, randomized study. Between 2005 and 2010, 100 operable cervical cancer patients of FIGO stage I/A2 (n=4), I/B1 (n=51), I/B2 (n=19), IIA (n=17), and proximal II/B (n=9) were randomized in two arms: in arm "A" (n=50) allocated treatment was 2x8 Gy preoperative intracavitary HDR BT followed by radical surgery, in arm "B" (n= 50) no preoperative treatment was given before the planned radical Wertheim hysterectomy. The rates of pathologic complete remission (pCR) were compared using the Fisher-exact test. In arm "A" 41 patients (82%), in arm "B" 42 patients (84%) underwent radical hysterectomy. The rate of pCR after preoperative BT was 26.8% (11/41), while in the control group the specimen was free of tumor in 7.1% (3/42; p=0.0204). Preoperative HDR BT for cervical cancer patients significantly increases the rate of pathologically tumor-free specimens. Longer follow-up is needed to evaluate the impact of pCR on local tumor control and survival. Our preliminary results support further enrollment of patients into our randomized clinical trial.

Primary radiotherapy of stage IIA/B-IIIB cervical carcinoma. A comparison of continuous versus sequential regimens.

BACKGROUND: Comprehensive literature on cervical cancer demonstrates, even today, the need for optimization of the timing of external-beam radiotherapy (EBRT) and high-dose-rate brachytherapy (HDR-BT) in the treatment of stage IIA/B-IIIB cervical carcinoma. PATIENTS AND METHODS: 210 patients with carcinoma of the cervix were treated in the Municipal Center of Oncoradiology between January 1991 and December 1996 (FIGO IIA: n = 10, FIGO IIB: n = 113, and FIGO IIIB: n = 87). Two regimens were compared: sequential radiation therapy (SRT) with 4 x 8 Gy HDR-BT to point A followed by EBRT, and continuous radiation therapy (CRT) in which 5 x 6 Gy HDR-BT to point A, one session per week, was integrated into the EBRT. A total dose of 68-70 Gy to point A and 52-54 Gy to point B was given in EBRT with SRT, five fractions per week were applied. Four fractions per week were applied in CRT, i. e., no EBRT was performed on the day of HDR-BT. Total doses to points A and B were identical in both regimens. Overall treatment time (OTT) amounted to 56 days for SRT and 35 days for CRT. Median follow-up time was 3.4 (2.5-4.2) years. RESULTS: Progression-free 5-year-survival (PFS) was 71% in the CRT and 56% in the SRT group. Nevertheless, this difference was not statistically significant (p = 1.00), and the same was found in a subgroup analysis of the different tumor stages, showing, however, an unequivocal trend. Late bladder and rectal injuries occurred in 13% and 25%, respectively. Late rectal injuries were significantly more frequent with SRT than CRT (35 patients in the SRT and 18 patients in the CRT group; p = 0.037). This was due to the higher doses per fraction of HDR-BT in the SRT group. No difference was found regarding late bladder injuries (p = 0.837). CONCLUSION: For the patients included in this study, no advantage has been found so far in using CRT, i. e., shortening the OTT by weekly integration of HDR-BT into EBRT. Nevertheless, an obvious trend exists. The dose of 8 Gy per fraction of HDR-BT in the SRT regimen was obviously too high. To achieve a significant improvement in local control and disease-free survival (DFS) as well as overall survival (OS), the combination with modern chemotherapy regimens and regional deep hyperthermia may rather be the treatment option.