Publications by authors named "Marjaana Luukkaa"

12 Publications

  • Page 1 of 1

Biweekly Cabazitaxel Is a Safe Treatment Option for Metastatic Castration-resistant Prostate Cancer (mCRPC) Patients After Docetaxel - A Final Analysis of the Prosty II Trial.

Anticancer Res 2020 Dec 7;40(12):6915-6921. Epub 2020 Dec 7.

4Pharma Ltd., Turku, Finland.

Background/aim: Our phase III trial showed that biweekly docetaxel (D) is better tolerated than triweekly D in metastatic castration-resistant prostate cancer (mCRPC). The safety of biweekly cabazitaxel (CBZ) post-docetaxel was studied in mCRPC.

Patients And Methods: Altogether, 60 patients received CBZ 16 mg/m i.v. on day 1 and day 14 of a 4-week cycle. The mean serum PSA levels were 305 ng/ml, and the mean age 67 years. The primary endpoint was safety according to CTCAEv4.0.

Results: A total of 255 4-week cycles of CBZ were administered. The most common grade 3/4 adverse events were neutropenia (16.7%), pain (13.3%), fatigue (10.0%), anemia (5.0%) and non-neutropenic infection (10.0%). PSA responses occurred in 10 patients (16.7%). Clinical benefit rate was 38.3% and median survival 10 months.

Conclusion: Biweekly CBZ is a well-tolerated treatment resulting in meaningful benefits for heavily pretreated mCRPC patients.
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http://dx.doi.org/10.21873/anticanres.14715DOI Listing
December 2020

2-Weekly versus 3-weekly docetaxel to treat castration-resistant advanced prostate cancer: a randomised, phase 3 trial.

Lancet Oncol 2013 Feb 4;14(2):117-24. Epub 2013 Jan 4.

Department of Oncology, Tampere University Hospital, Tampere, Finland.

Background: Docetaxel administered every 3 weeks is a standard treatment for castration-resistant advanced prostate cancer. We hypothesised that 2-weekly administration of docetaxel would be better tolerated than 3-weekly docetaxel in patients with castration-resistant advanced prostate cancer, and did a prospective, multicentre, randomised, phase 3 study to compare efficacy and safety.

Methods: Eligible patients had advanced prostate cancer (metastasis, a prostate-specific-antigen test result of more than 10·0 ng/mL, and WHO performance status score of 0-2), had received no chemotherapy (except with estramustine), had undergone surgical or chemical castration, and had been referred to a treatment centre in Finland, Ireland, or Sweden. Enrolment and treatment were done between March 1, 2004, and May 31, 2009. Randomisation was done centrally and stratified by centre and WHO performance status score of 0-1 vs 2. Patients were assigned 75 mg/m(2) docetaxel intravenously on day 1 of a 3-week cycle, or 50 mg/m(2) docetaxel intravenously on days 1 and 15 of a 4-week cycle. 10 mg oral prednisolone was administered daily to all patients. The primary endpoint was time to treatment failure (TTTF). We assessed data in the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT00255606.

Findings: 177 patients were randomly assigned to the 2-weekly docetaxel group and 184 to the 3-weekly group. 170 patients in the 2-weekly group and 176 in the 3-weekly group were included in the analysis. The 2-weekly administration was associated with significantly longer TTTF than was 3-weekly administration (5·6 months, 95% CI 5·0-6·2 vs 4·9 months, 4·5-5·4; hazard ratio 1·3, 95% CI 1·1-1·6, p=0·014). Grade 3-4 adverse events occurred more frequently in the 3-weekly than in the 2-weekly administration group, including neutropenia (93 [53%] vs 61 [36%]), leucopenia (51 [29%] vs 22 [13%]), and febrile neutropenia (25 [14%] vs six [4%]). Neutropenic infections were reported more frequently in patients who received docetaxel every 3 weeks (43 [24%] vs 11 [6%], p=0·002).

Interpretation: Administration of docetaxel every 2 weeks seems to be well tolerated in patients with castration-resistant advanced prostate cancer and could be a useful option when 3-weekly single-dose administration is unlikely to be tolerated.

Funding: Sanofi.
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http://dx.doi.org/10.1016/S1470-2045(12)70537-5DOI Listing
February 2013

Biweekly docetaxel is better tolerated than conventional three-weekly dosing for advanced hormone-refractory prostate cancer.

Anticancer Res 2012 Mar;32(3):953-6

Tampere University Hospital, Tampere, Finland.

Background: Docetaxel administered every three weeks is the standard treatment for advanced hormone-refractory prostate cancer (HRPC). However, biweekly administration might be better tolerated due to the reduced peak drug concentrations. Therefore, we compared biweekly to triweekly docetaxel as first- or second-line chemotherapy for advanced HRPC in this prospective randomized multicenter trial.

Patients And Methods: In this study, 360 patients were randomly allocated to receive docetaxel 75 mg/m(2) i.v. d1 q3 weeks (tT) or 50 mg/m(2) i.v. d1 and d 14, q4 weeks (bT) from March 2004 to May 2009. Oral prednisolone (10 mg/day) was administered in both groups. The groups were well balanced according to the WHO performance status in terms of mean age (70 vs. 68, range 45-87 years) and median serum PSA level at the time of study entry (109 vs. 98 μg/l, range 11-1490 μg/l). The primary endpoint was time to treatment failure (TTF). ClinicalTrials.gov study identifier: NCT00255606.

Results: Ultimately, 158 patients (tT=79; bT=79) were included in this preplanned interim safety analysis; 567 and 487 cycles (equivalent to 1701 and 1948 weeks of treatment) were administered in the tT and bT groups, respectively. The most common grade 3-4 adverse events (expressed as %/cycles) in tT /bT were neutropenia 20%/14%; infection with/without neutropenia 8%/3%; fatigue 3%/3%; febrile neutropenia 2%/1%; and bone pain 2%/1%. Serious adverse events occurred more frequently in the group tT (n=60, 10.6% of cycles) than in the group bT (n=29, 6.0%, p=0.012). One patient died due to coronary infarction, and another was diagnosed with acute lymphocytic leukemia (both in the bT group). Thirty patients (38%) in the bT group and 22 patients (28%) in the tT group were still receiving treatment at 6 months (p=0.176).

Conclusion: Biweekly docetaxel was tolerated better than conventional triweekly with fewer serious adverse events and more patients were still on the therapy at 6 months. Biweekly docetaxel therapy might be considered as an option for elderly patients exhibiting a compromised general condition.
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March 2012

Expression of the cellular oxygen sensor PHD2 (EGLN-1) predicts radiation sensitivity in squamous cell cancer of the head and neck.

Int J Radiat Biol 2009 ;85(10):900-8

Department of Oncology and Radiotherapy, Turku University Hospital, Turku, Finland.

Purpose: Prolyl hydroxylase domain proteins constitute a family of oxygen sensors that regulate the expression of hypoxia-inducible factor-1 alpha (HIF-1alpha), which mediates transcription of many genes under low oxygen concentration. PHD2 (Prolyl hydroxylase domain protein 2) isoform is the main regulator of HIF-1alpha degradation in normoxia and mild hypoxia. The aim of our study was to evaluate the relationship between expression of PHD2 and radiosensitivity in squamous cell cancer of the head and neck (HNSCC).

Patients And Methods: Paraffin embedded sections from untreated primary tumours were obtained for immunohistochemistry in 48 HNSCC patients scheduled for preoperative radiotherapy (RT). Nuclear expression of PHD2 was evaluated as a percentage of tumour cells showing positively stained nucleus. RT was a split-course accelerated hyperfractionated regimen (1.6 Gy twice a day) in 15 patients and standard in 33 patients. Viability of cancer cells was routinely evaluated histologically from resected tumours at planned surgery 3-4 weeks after RT. The follow-up time after multimodality treatment was five years or until death.

Results: PHD2 expression was low in normal tissues and well differentiated tumours. The expression was increased and predominantly nuclear in poorly differentiated tumours. In tumours later found to be sterilised by RT, nuclear PHD2 expression was markedly lower as compared to tumours showing viable cells at surgery (p = 0.04). A low nuclear staining of PHD2 (<10% of PHD2-positive nuclei) in the primary tumour was found to associate with good radiation response (p = 0.005).

Conclusions: We found low PHD2 expression and in particular low nuclear expression to predict a favourable response to RT. Therefore, nuclear PHD2 expression may act as a surrogate marker for radiation resistance in HNSCC.
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http://dx.doi.org/10.1080/09553000903074104DOI Listing
July 2010

Pim-1 kinase expression predicts radiation response in squamocellular carcinoma of head and neck and is under the control of epidermal growth factor receptor.

Neoplasia 2009 Jul;11(7):629-36

Turku Centre for Biotechnology, University of Turku and Abo Akademi University, Turku, Finland.

Pim-1 is an oncogenic serine/threonine kinase with poorly defined function in epithelial cancers. In this study, we determined 1) associations of Pim-1 expression with clinicopathological parameters including responsiveness to irradiation in squamocellular cancers of head and neck and 2) how Pim-1 expression is controlled subsequent to irradiation. Moderate to high expression of Pim-1 correlated to poor response to radiation therapy (P = .003). It is also associated to the expression of epidermal growth factor receptor (EGFR, P < .0001), which has been shown to be activated by irradiation. In radioresistant tumors, irradiation promoted nuclear translocation of Pim-1 (P < .005). When directly testing EGFR dependence of Pim-1 expression, up-regulation and nuclear translocation of Pim-1 could be induced through stimulation of EGFR with its ligands EGF or transforming growth factor alpha. Both ligand- and irradiation-induced changes in Pim-1 expression and localization could be inhibited by the monoclonal anti-EGFR antibody cetuximab and by the tyrosine kinase inhibitor gefitinib also targeting EGFR. These results suggest that irradiation-induced activation of EGFR upregulates Pim-1, and Pim-1 may be used as a novel predictive marker of radiation response in patients with squamocellular cancers of head and neck.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2697349PMC
http://dx.doi.org/10.1593/neo.81038DOI Listing
July 2009

Squamous cell carcinomas arising from different types of oral epithelia differ in their tumor and patient characteristics and survival.

Oral Oncol 2007 Oct 25;43(9):911-9. Epub 2007 Jan 25.

Department of Oral and Maxillofacial Surgery, Institute of Dentistry, University of Turku, Lemminkäisenkatu 2, FIN-20520 Turku, Finland.

A hypothesis that OSCCs originating from different types of oral epithelia may have different patient and tumor characteristics was evaluated in this retrospective analysis of 188 patients with primary OSCC treated at Turku University Central Hospital, Turku, Finland in 1988-1997. The tumors were categorized according to the type of oral epithelium from which they have originated: (1) specialized epithelium (dorsal tongue) (2) keratinized (masticatory) epithelium, (3) non-keratinized (lining) epithelium, and (4) tongue epithelium (epithelium on the lateral border of the tongue). The relevant clinical data, including age, sex, social status, and risk behavior of the patients and clinical presentation, histopathological grading, and treatment of the tumors, as well as the follow-up information, were collected from the patient charts of the hospital. In general, tumor and patient characteristics of OSCCs and survival rates were found to be in line with those of recent analyses reported from other industrialized countries. However, OSCCs in young patients (4.8%) seemed to be clinically at a lower stage and histologically more highly differentiated than those of the other patients. Eight out of 9 (89%) OSCCs in the young patients were located on the lateral tongue. The 5-year recurrence-free rates of the patients according to the epithelial origin of the tumors were as follows: masticatory epithelium 42%, lining epithelium 57%, and epithelium of the lateral border of the tongue 61%. In conclusion, the tumors originating from different types of oral epithelia may have distinct properties with regard to their clinical behavior and responsiveness to the different treatment modalities. It would seem to be meaningful to investigate the molecular characteristics of the different types of oral epithelium in order to elucidate possible differences in their susceptibility to malignant transformation.
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http://dx.doi.org/10.1016/j.oraloncology.2006.11.012DOI Listing
October 2007

Oral tongue carcinoma and its treatment in Finland.

Eur Arch Otorhinolaryngol 2007 Mar 21;264(3):263-7. Epub 2006 Sep 21.

Department of Otorhinolaryngology, Head and Neck Surgery, Helsinki University Central Hospital, Helsinki, Finland.

Management of oral tongue squamous cell cancer (OTSCC) remains a challenge. This nationwide study reports the used treatment approach and the outcome of OTSCC in Finland. Retrospective study of OTSCC patients in 1995-1999 with a 5-year follow-up. The corresponding data from 1980 to 1989 is also included. About 235 patients (125 M, 110 F; mean age 61.6 years; range 24-90 years) were included, 77% had SCC of lateral border of the tongue and 25% were N+. Treatment with curative intent was given to 224 (95%) patients. Surgery of the primary tumour was performed in 218 (97%) patients and with a reconstruction in 69 (31%) patients. A neck dissection was performed ipsilaterally in 114 (51%) and bilaterally in 9 (4%) cases. Irradiation was given to 131 (58%) patients. The rate for locoregional recurrence was 28%. The 3- and 5-year overall survival (OS) rates were 66 and 47%, respectively. The corresponding disease specific survival (DSS) rates were 74 and 64%, respectively. The mean DSS for patients younger than 40 years and older than 40 years was 111 and 88 months, respectively (P < 0.02). The 3- and 5-year DSS rates were: Stage I, 88 and 74%; Stage II, 74 and 62%; Stage III, 79 and 71% and Stage IV, 36 and 33%, respectively. In the present study the surgical treatment approach seems effective in controlling early stage OTSCC but the modest survival, in spite of combination of radiotherapy and surgery, points out the need to consider new strategies in the management of advanced stage disease.
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http://dx.doi.org/10.1007/s00405-006-0158-zDOI Listing
March 2007

Overexpression and nuclear translocation of hypoxia-inducible factor prolyl hydroxylase PHD2 in head and neck squamous cell carcinoma is associated with tumor aggressiveness.

Clin Cancer Res 2006 Feb;12(4):1080-7

Turku Centre for Biotechnology, Turku University, Finland.

Purpose: Hypoxia in tumors is associated with poor prognosis and resistance to treatment. The outcome of hypoxia is largely regulated by the hypoxia-inducible factors (HIF-1alpha and HIF-2alpha). HIFs in turn are negatively regulated by a family of prolyl hydroxylases (PHD1-3). The PHD2 isoform is the main down-regulator of HIFs in normoxia and mild hypoxia. This study was designed to analyze the correlation of the expression and subcellular localization of PHD2 with the pathologic features of human carcinomas and HIF-1alpha expression.

Experimental Design: The expression of PHD2 was studied from paraffin-embedded normal tissue (n = 21) and head and neck squamous cell carcinoma (HNSCC; n = 44) by immunohistochemistry. Further studies included PHD2 mRNA detection and HIF-1alpha immunohistochemistry from HNSCC specimens as well as PHD2 immunocytochemistry from HNSCC-derived cell lines.

Results: In noncancerous tissue, PHD2 is robustly expressed by endothelial cells. In epithelium, the basal proliferating layer also shows strong expression, whereas the more differentiated epithelium shows little or no PHD2 expression. In HNSCC, PHD2 shows strongly elevated expression both at the mRNA and protein level. Moreover, PHD2 expression increases in less differentiated phenotypes and partially relocalizes from the cytoplasm into the nucleus. Endogenously high nuclear PHD2 is seen in a subset of HNSCC-derived cell lines. Finally, although most of the tumor regions with high PHD2 expression show down-regulated HIF-1alpha, regions with simultaneous HIF-1alpha and PHD2 expression could be detected.

Conclusions: Our results show that increased levels and nuclear translocation of the cellular oxygen sensor, PHD2, are associated with less differentiated and strongly proliferating tumors. Furthermore, they imply that even the elevated PHD2 levels are not sufficient to down-regulate HIF-1alpha in some tumors.
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http://dx.doi.org/10.1158/1078-0432.CCR-05-2022DOI Listing
February 2006

Association between high collagenase-3 expression levels and poor prognosis in patients with head and neck cancer.

Head Neck 2006 Mar;28(3):225-34

Department of Oncology and Radiotherapy, Turku University Hospital, P.O. Box 52, FIN-20521 Turku, Finland.

Background: Squamous cell carcinoma of the head and neck (HNSCC) is a common cancer type. The ability for curative treatment with surgery and radiotherapy (RT) is usually highly dependent on tumor stage at the time of diagnosis.

Methods: The purpose of this study was to determine whether the expression of a cancer-specific proteinase, collagenase-3 (matrix metalloproteinase-13 [MMP-13]), is associated with survival parameters in patients with HNSCC. We studied MMP-13 expression in tumors of 81 patients with stage I-IV HNSCC treated with surgery alone or in combination with radiotherapy.

Results: We found a subgroup of patients with high MMP-13 expression level in their tumors (>/=90% MMP-13-positive tumor cells) associated with unfavorable prognosis (median overall survival [OS], 11.8 vs 19.6 months, p = .032). In addition, the median disease-specific survival (DSS) time was markedly reduced in this subgroup (13.8 months vs 40.7 months, p = .062). When the subgroup of patients treated with a curative intent was studied, the same association was found in OS (13.8 vs 24.6 months, p = .023) and DSS (p = .004). In addition, there was a trend for association between >/=90% MMP-13 positivity and a recurrent tumor (p = .078) in curatively treated patients.

Conclusions: The short survival time associated with high MMP-13 expression levels could not be predicted by tumor size or local lymph node invasion. These results show that a high MMP-13 expression level is associated with aggressiveness of HNSCC and may have prognostic value in patient evaluation.
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http://dx.doi.org/10.1002/hed.20322DOI Listing
March 2006

Treatment of squamous cell carcinoma of the oral cavity, oropharynx and hypopharynx--an analysis of 174 patients in south western Finland.

Acta Oncol 2003 ;42(7):756-62

Department of Oncology and Radiotherapy, Turku University Central Hospital, Turku, Finland.

The purpose of this study was to determine the efficacy and feasibility of full-dose preoperative radiation therapy (RT) in head and neck cancer presenting in the oral cavity, oro- and hypopharynx, within a single university hospital district. During a seven-year period, 1989 to 1995, 174 patients with squamous cell carcinoma (SCC) of the oral cavity (OC, 70% of all patients), oropharynx (OP, 15%) and hypopharynx (HP, 15%) were referred to Turku University Central Hospital. All patients were seen by a tumor board consisting of an ENT (ear-nose-throat) head and neck surgeon, a radiation oncologist and a dentist. Potentially curative treatment was given to 142 patients. Of these, 88 (62%) had preoperative RT, 6 (4%) postoperative RT, 34 (24%) definitive RT and 14 patients (10%) were treated with surgery only. The radiation dose was > or = 50 Gy. averagely 64 Gy. The major endpoints of the study were local control, overall survival and major complications of the combined treatment. The 5-year relative survival rate (RSR) was 40% for all, and 43% for patients treated with curative intent. For these, the local control at 5 years was 60%; the disease-specific 5-year survival rate was 65% for the patients with lingual SCC, 45% for those with other oral tumor localizations. 64% for the oropharynx patients and 47% for those with tumor in their hypopharynx, while it was 55% for all patients. The preoperative radiotherapy was fairly well tolerated. Ten (7%) of the patients treated with curative intent suffered major complications, and four patients had evidence of osteoradionecrosis. With the exception of patients with early SCC the outcome remains rather poor in this group of cancer patients who often have marked co-morbidity. In our opinion, preoperative radiotherapy to a dose of 62-64 Gy can safely be given, and remains a feasible means to treat patients with oral, oropharyngeal or hypopharyngeal cancer.
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http://dx.doi.org/10.1080/02841860310010907DOI Listing
January 2004

Intratumoral lymphatics are essential for the metastatic spread and prognosis in squamous cell carcinomas of the head and neck region.

Cancer Res 2003 Apr;63(8):1920-6

The National Public Health Institute, Turku University School of Biomedical Sciences, Department of Medical Microbiology and the MediCity Research Laboratory, Turku University, FIN-20520 Turku, Finland.

Head and neck squamous cell carcinomas (HNSCCs) frequently disseminate to regional lymph nodes. To investigate the possible mechanisms involved, we studied the expression of cancer cell adhesion molecules together with lymphatic vascular and blood vascular markers in a panel of 97 primary HNSCC tumors and correlated expression levels with conventional clinicopathological parameters and with long-term prognosis. In particular, we measured the density of intratumoral and peritumoral lymph vessels as assessed with the marker lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) and the density of tumor CD44, a receptor up-regulated in many metastatic cancers. Intratumoral LYVE-1(+) lymphatic vessels were clearly associated with a higher risk for local relapse as well as with poor disease-specific prognosis (P = 0.02 and 0.0009, respectively). In contrast, a high density of peritumoral LYVE-1(+) vessels was a sign of favorable survival (P = 0.05). Strong primary tumor CD44 expression was associated with a poor prognosis, an increased risk of local recurrence (P = 0.03 and 0.02, respectively), and an increase in resistance to radiation therapy (P = 0.03). CD44 was the only factor with an independent prognostic value for the disease-specific overall survival (P = 0.04). Our results suggest that intratumoral lymphatics play a greater role than peritumoral lymphatics in nodal metastasis of HNSCC and that tumor CD44 levels can predict sensitivity to radiation therapy. These parameters may be useful predictive and prognostic tools in the clinical management of HNSCC.
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April 2003

Neodymium YAG contact laser in the treatment of cancer of the mobile tongue.

Acta Otolaryngol 2002 Apr;122(3):318-22

Department of Oncology, Turku University Central Hospital, Finland.

The aim of this study was to evaluate the usefulness of a contact neodymium YAG laser for the treatment of squamous cell carcinoma (SCC) of the mobile tongue in 35 patients. The TNM stage and histologic grade were as follows: T1, n = 20; T2, n = 11; T3, n = 4; and N0, n = 33; N1, n = 2; G1, n = 20; G2, n = 10; and G3, n = 5. The surgical treatment consisted of a hemiglossectomy or resection with adequate margins in 28 cases, and an ipsilateral neck dissection was also performed in 7 patients. Radiotherapy to a mean tumor dose of 62-64 Gy and an elective dose of 50 Gy to the cervical lymph nodes was given to 14 patients. The radiotherapy was preoperative in 12 patients and postoperative in 2. Tongue resection was easily performed using the contact neodymium YAG laser, with a mean operation time of 31 min and intraoperative bleeding varying from negligible to 100 cm3. During postoperative follow-up no major complications occurred: cases with minor hemorrhage were easily controlled on the ward and 1 patient had a bleed on the 14th postoperative day necessitating hospitalization. The resection was histologically radical in all cases. During follow-up one patient had a local recurrence (T2N0, G3) and four failed in the neck (T1N0 G2, T1N0 G2, T1N0 G2, T2N0 G2), three of whom were successfully salvaged with a neck dissection and radiotherapy. One patient with osteoradionecrosis was diagnosed and treated curatively. Two patients died of their tongue cancer (T2N0 G3, T2N0 G2), 1 died from a second primary tumor (T2N0 G1) and 2 of intercurrent disease with no evidence of cancer; 30 patients (86%) are still alive with no evidence of disease. The function of the tongue in all patients in this sample was good to satisfactory. The major complaint was xerostomia in the irradiated patients. In conclusion, the contact neodymium YAG laser appears to be suitable for resection of T1-T2 SCCs of the oral tongue. In this limited patient sample T stage or grade did not predict failures in the neck. Biologic predictive markers need to be evaluated.
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http://dx.doi.org/10.1080/000164802753648240DOI Listing
April 2002