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Radu, Calin
Publications (7 of 7) Show all publications
Erlandsson, J., Holm, T., Pettersson, D., Berglund, Å., Cedermark, B., Radu, C., . . . Martling, A. (2017). Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): a multicentre, randomised, non-blinded, phase 3, non-inferiority trial. The Lancet Oncology, 18(3), 336-346
Open this publication in new window or tab >>Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): a multicentre, randomised, non-blinded, phase 3, non-inferiority trial
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2017 (English)In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 18, no 3, p. 336-346Article in journal (Refereed) Published
Abstract [en]

Background: Radiotherapy reduces the risk of local recurrence in rectal cancer. However, the optimal radiotherapy fractionation and interval between radiotherapy and surgery is still under debate. We aimed to study recurrence in patients randomised between three different radiotherapy regimens with respect to fractionation and time to surgery.

Methods: In this multicentre, randomised, non-blinded, phase 3, non-inferiority trial (Stockholm III), all patients with a biopsy-proven adenocarcinoma of the rectum, without signs of non-resectability or distant metastases, without severe cardiovascular comorbidity, and planned for an abdominal resection from 18 Swedish hospitals were eligible. Participants were randomly assigned with permuted blocks, stratified by participating centre, to receive either 5 x 5 Gy radiation dose with surgery within 1 week (short-course radiotherapy) or after 4-8 weeks (short-course radiotherapy with delay) or 25 x 2 Gy radiation dose with surgery after 4-8 weeks (long-course radiotherapy with delay). After a protocol amendment, randomisation could include all three treatments or just the two short-course radiotherapy treatments, per hospital preference. The primary endpoint was time to local recurrence calculated from the date of randomisation to the date of local recurrence. Comparisons between treatment groups were deemed non-inferior if the upper limit of a double-sided 90% CI for the hazard ratio (HR) did not exceed 1.7. Patients were analysed according to intention to treat for all endpoints. This study is registered with ClinicalTrials.gov, number NCT00904813.

Findings: Between Oct 5, 1998, and Jan 31, 2013, 840 patients were recruited and randomised; 385 patients in the three-arm randomisation, of whom 129 patients were randomly assigned to short-course radiotherapy, 128 to short-course radiotherapy with delay, and 128 to long-course radiotherapy with delay, and 455 patients in the two-arm randomisation, of whom 228 were randomly assigned to short-course radiotherapy and 227 to short-course radiotherapy with delay. In patients with any local recurrence, median time from date of randomisation to local recurrence in the pooled short-course radiotherapy comparison was 33.4 months (range 18.2-62.2) in the short-course radiotherapy group and 19.3 months (8.5-39.5) in the short-course radiotherapy with delay group. Median time to local recurrence in the long-course radiotherapy with delay group was 33.3 months (range 17.8-114.3). Cumulative incidence of local recurrence in the whole trial was eight of 357 patients who received short-course radiotherapy, ten of 355 who received short-course radiotherapy with delay, and seven of 128 who received long-course radiotherapy (HR vs short-course radiotherapy: short-course radiotherapy with delay 1.44 [95% CI 0.41-5.11]; long-course radiotherapy with delay 2.24 [0.71-7.10]; p=0.48; both deemed non-inferior). Acute radiation-induced toxicity was recorded in one patient (<1%) of 357 after short-course radiotherapy, 23 (7%) of 355 after short-course radiotherapy with delay, and six (5%) of 128 patients after long-course radiotherapy with delay. Frequency of postoperative complications was similar between all arms when the three-arm randomisation was analysed (65 [50%] of 129 patients in the short-course radiotherapy group; 48 [38%] of 128 patients in the short-course radiotherapy with delay group; 50 [39%] of 128 patients in the long-course radiotherapy with delay group; odds ratio [OR] vs short-course radiotherapy: short-course radiotherapy with delay 0.59 [95% CI 0.36-0.97], long-course radiotherapy with delay 0.63 [0.38-1.04], p=0.075). However, in a pooled analysis of the two short-course radiotherapy regimens, the risk of postoperative complications was significantly lower after short-course radiotherapy with delay than after short-course radiotherapy (144 [53%] of 355 vs 188 [41%] of 357; OR 0.61 [95% CI 0.45-0.83] p=0.001).

Interpretation: Delaying surgery after short-course radiotherapy gives similar oncological results compared with short-course radiotherapy with immediate surgery. Long-course radiotherapy with delay is similar to both short-course radiotherapy regimens, but prolongs the treatment time substantially. Although radiation-induced toxicity was seen after short-course radiotherapy with delay, postoperative complications were significantly reduced compared with short-course radiotherapy. Based on these findings, we suggest that short-course radiotherapy with delay to surgery is a useful alternative to conventional short-course radiotherapy with immediate surgery.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-318940 (URN)10.1016/S1470-2045(17)30086-4 (DOI)000396344600045 ()28190762 (PubMedID)
Funder
Swedish Research CouncilSwedish Cancer SocietyStockholm County Council
Available from: 2017-04-03 Created: 2017-04-03 Last updated: 2017-11-29Bibliographically approved
Leon, O., Guren, M. G., Radu, C., Gunnlaugsson, A. & Johnsson, A. (2015). Phase I study of cetuximab in combination with 5-fluorouracil, mitomycin C and radiotherapy in patients with locally advanced anal cancer. European Journal of Cancer, 51(18), 2740-2746
Open this publication in new window or tab >>Phase I study of cetuximab in combination with 5-fluorouracil, mitomycin C and radiotherapy in patients with locally advanced anal cancer
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2015 (English)In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 51, no 18, p. 2740-2746Article in journal (Refereed) Published
Abstract [en]

Background: 5-fluorouracil (5FU) and mitomycin C (MMC)-based chemoradiotherapy (CRT) is standard treatment for anal squamous cell carcinoma. In this phase I study cetuximab was added and the primary aim was to determine the maximum tolerated dose (MTD) of 5FU and MMC in this combination. Methods and materials: Patients with locally advanced anal cancer, T2 (> 4 cm) -4N0-3M0, received weekly standard doses of cetuximab starting 1 week before CRT. Intensity modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) with simultaneous integrated boost (SIB) was given to 57.5/54.0/48.6 Gy in 27 fractions to primary tumour/lymph node metastases/adjuvant lymph node regions. 5FU/MMC was given concomitantly on RT weeks 1 and 5 according to a predefined dose escalation schedule. Results: Thirteen patients were enrolled. Two patients discontinued cetuximab due to hypersensitivity reaction. The median age was 65 years (range 46-70), nine were females, and 85% had stage IIIB disease. Dose-limiting toxicity events (diarrheoa, febrile neutropenia and thrombocytopenia) occurred in 3 of 11 patients. The most common grade 3-4 side-effects were radiation dermatitis (63%), haematologic toxicity (54%), and diarrheoa (36%). No treatment-related deaths occurred. Three months following completion of treatment, ten patients (91%) had a local complete remission (CR), but two patients had developed liver metastases, yielding a total CR rate of 73%. Conclusion: The MTDs were determined as 5FU 800 mg/m(2) on RT days 1-4 and 29-32 and MMC 8 mg/m(2) on days 1 and 29 when combined with IMRT/VMAT with SIB and cetuximab in locally advanced anal cancer.

Keywords
Anal cancer, 5-Fluorouracil, Mitomycin C, Cetuximab, Phase I, Radiotherapy
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-270940 (URN)10.1016/j.ejca.2015.08.029 (DOI)000365624500003 ()26597443 (PubMedID)
Available from: 2016-01-05 Created: 2016-01-05 Last updated: 2017-12-01Bibliographically approved
Radu, C., Norrlid, O., Braendengen, M., Hansson, K., Isacsson, U. & Glimelius, B. (2013). Integrated peripheral boost in preoperative radiotherapy for the locally most advanced non-resectable rectal cancer patients. Acta Oncologica, 52(3), 528-537
Open this publication in new window or tab >>Integrated peripheral boost in preoperative radiotherapy for the locally most advanced non-resectable rectal cancer patients
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2013 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 52, no 3, p. 528-537Article in journal (Refereed) Published
Abstract [en]

Background and Purpose.

Few studies have explored the potential clinical advantages of dose escalation and integrated boosts for patients with non-resectable locally advanced rectal cancer. The possibility of escalating dose to non-resectable regions in these patients was the aim of this study.

Patients and methods.

Seven patients with locally very advanced rectal tumours (sacrum overgrowth or growth into pelvic side walls) were evaluated. Intensity modulated photon and pencil beam scanning proton plans with simultaneously integrated boosts (45 Gy to elective lymph nodes, 50 Gy to tumour and 62.5 Gy to boost area in 25 fractions) were compared.

Results.

Target coverage was achieved with both photon and proton plans. Estimated risks of acute side effects put the two patients with the largest tumours at unacceptable risk for intestinal toxicity, regardless of modality. The remaining five patients had beneficial sparing of dose to the small intestine with protons.

Conclusions.

Adding boost to areas where rectal tumours infiltrate adjacent non-resectable organs is an attractive option which appears possible using both photon and proton irradiation. Proton plans reduced dose to organs at risk. Integrated peripheral boosts should be considered more frequently in these very advanced tumours.

Place, publisher, year, edition, pages
Informa Healthcare, 2013
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:uu:diva-187668 (URN)10.3109/0284186X.2012.737022 (DOI)000316123200011 ()23113591 (PubMedID)
Available from: 2012-12-10 Created: 2012-12-10 Last updated: 2017-12-07Bibliographically approved
Radu, C. (2012). Optimising Radiotherapy in Rectal Cancer Patients. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Optimising Radiotherapy in Rectal Cancer Patients
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Rectal cancer is the eight most common cancer diagnosis in Sweden in both men and women, with almost 2000 new cases per year. Radiotherapy, which is an important treatment modality for rectal cancer, has evolved during the past decades. Diagnostic tools have also improved, allowing better staging and offering information used to make well-founded decisions in multidisciplinary team conferences.

In a retrospective study (n=46) with locally advanced rectal cancer (LARC) patients, unfit for chemoradiotherapy, patients were treated with short-course radiotherapy. Delayed surgery was done when possible. Radical surgery was possible in 89% of the patients who underwent surgery (80%). Grade IV diarrhoea affected three elderly patients. Target radiation volume should be reduced in elderly or metastatic patients.

In a prospective study (n=68) with LARC patients, magnetic resonance imaging (MRI) and 2-18F-fluoro-2-D-deoxyglucose (FDG) positron emission tomography (PET) were used to determine if FDG-PET could provide extra treatment information. Information from FDG-PET changed the stage of 10 patients. Delineation with FDG-PET generally resulted in smaller target volumes than MRI only.

Seven of the most advanced LARC patients in the above cohort were used for a methodological study to determine if dose escalation to peripheral, non-resectable regions was feasible. Simultaneous integrated boost plans with photons and protons were evaluated. While toxicity was acceptable in five patients with both protons and photons, two patients with very large tumours had unacceptable risk for intestinal toxicity regardless of modality.

In the interim analysis of the Stockholm III Trial (n=303, studying radiotherapy-fractionation and timing of surgery in relation to radiotherapy) compliance was acceptable and severe acute toxicity was infrequent, irrespective of fractionation. Short-course radiotherapy with immediate surgery tended to give more postoperative complications, but only if surgery was delayed more than 10 days after the start of radiotherapy.

Quality-of-life in the Stockholm III Trial was studied before, during and shortly after treatment using the EORTC QLQ-C30 and CR38 questionnaires. Surgery accounted for more adverse effects than radiotherapy in all groups. Postoperatively, the poorest quality-of-life was seen in patients given short-course radiotherapy followed by immediate surgery. No postoperative differences were seen between the two groups with delayed surgery.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. p. 57
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 775
Keywords
Rectal cancer, locally advanced, radiotherapy, FDG-PET, peripheral boost, protons, quality-of-life
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:uu:diva-172531 (URN)978-91-554-8367-8 (ISBN)
Public defence
2012-06-11, Skoogsalen, Akademiska Sjukhuset, ingång 78, Uppsala, 13:15 (Swedish)
Opponent
Supervisors
Available from: 2012-05-21 Created: 2012-04-11 Last updated: 2012-08-01Bibliographically approved
Brændengen, M., Hansson, K., Radu, C., Siegbahn, A., Jacobsson, H. & Glimelius, B. (2011). Delineation of gross tumor volume (GTV) for radiation treatment planning of locally advanced rectal cancer using information from MRI or FDG-PET/CT: a prospective study. International Journal of Radiation Oncology, Biology, Physics, 81(4), e439-e445
Open this publication in new window or tab >>Delineation of gross tumor volume (GTV) for radiation treatment planning of locally advanced rectal cancer using information from MRI or FDG-PET/CT: a prospective study
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2011 (English)In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 81, no 4, p. e439-e445Article in journal (Refereed) Published
Abstract [en]

PURPOSE:

Accurate delineation of target volumes is important to maximize radiation dose to the tumor and minimize it to nontumor tissue. Computed tomography (CT) and magnetic resonance imaging (MRI) are standard imaging modalities in rectal cancer. The aim was to explore whether functional imaging with F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET), combined with CT (FDG-PET/CT) gives additional information to standard pretreatment evaluation and changes the shape and size of the gross tumor volume (GTV).

METHODS AND MATERIALS:

From 2007 to 2009, 77 consecutive patients with locally advanced rectal cancer were prospectively screened for inclusion in the study at two university hospitals in Sweden, and 68 patients were eligible. Standard GTV was delineated using information from clinical examination, CT, and MRI (GTV-MRI). Thereafter, a GTV-PET was defined in the fused PET-CT, and the target volume delineations were compared for total volume, overlap, and mismatch. Pathologic uptake suspect of metastases was also registered.

RESULTS:

The median volume of GTV-MRI was larger than that of GTV-PET: 111 cm3 vs. 87 cm3 (p < 0.001). In many cases, the GTV-MRI contained the GTV defined on the PET/CT images as subvolumes, but when a GTV total was calculated after the addition of GTV-PET to GTV-MRI, the volume increased, with median 11% (range, 0.5–72%). New lesions were seen in 15% of the patients for whom PET/CT was used.

CONCLUSIONS:

FDG-PET/CT facilitates and adds important information to the standard delineation procedure of locally advanced rectal cancer, mostly resulting in a smaller GTV, but a larger total GTV using the union of GTV-MRI and GTV-PET. New lesions were sometimes seen, potentially changing the treatment strategy.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-169858 (URN)10.1016/j.ijrobp.2011.03.031 (DOI)000309412300031 ()21641122 (PubMedID)
Available from: 2012-03-06 Created: 2012-03-06 Last updated: 2017-12-07Bibliographically approved
Radu, C., Johansson, B., Pettersson, D., Martling, A. & Glimelius, B.Health-related quality-of-life during treatment in the Stockholm III Trial, evaluating different preoperative radiotherapy regimens for rectal cancer.
Open this publication in new window or tab >>Health-related quality-of-life during treatment in the Stockholm III Trial, evaluating different preoperative radiotherapy regimens for rectal cancer
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(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-172410 (URN)
Available from: 2012-04-10 Created: 2012-04-10 Last updated: 2012-08-01
Radu, C., Norrlid, O., Braendengen, M., Hansson, K., Isacsson, U. & Glimelius, B.Integrated peripheral boost in preoperative radiotherapy for the locally most advanced non-resectable rectal cancer patients.
Open this publication in new window or tab >>Integrated peripheral boost in preoperative radiotherapy for the locally most advanced non-resectable rectal cancer patients
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-172407 (URN)
Available from: 2012-04-10 Created: 2012-04-10 Last updated: 2012-08-01
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