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Background: Metastatic uveal melanoma (mUM) is an aggressive cancer predominately affecting the liver. Peritoneal metastases (PM) occur rarely, and there is limited knowledge about this subgroup´s clinical course and biology., Methods: We analyzed 41 mUM patients with confirmed PM from the Charité-Universitätsmedizin Berlin database, focusing on clinical characteristics, immune cell infiltrates, genetic alterations and tumor mutational burden (TMB)., Results: The incidence of PM in mUM was 4.27 %. Metastatic disease was diagnosed 3.6 years after primary UM, with PM developing later (median: 4.7 years). Median overall survival (OS) from mUM diagnosis was 22.4 months. Prognosis correlated with metastatic pattern. Patients presenting with synchronous liver and peritoneal metastases or primary hepatic metastases followed by secondary peritoneal dissemination showed a median OS of 19.7 and 17.7 months, respectively. However, PM patients with exclusive extrahepatic disease at diagnosis of mUM had a significantly longer OS of 48.6 months and this metastatic pattern showed highly significant correlation with low and intermediate genetic risk. Metastasis-free survival and OS upon mUM diagnosis were significantly shorter in patients with high-risk UM tumors. TMB also correlated with metastatic pattern, being lowest in patients presenting with only extrahepatic disease. Higher TMB was generally associated with shorter OS., Conclusion: PM in mUM patients is rare and in contrast to other extra-abdominal tumors does not worsen prognosis. Prognosis is greatly influenced by the metastatic pattern, which is determined by tumor biology, as evidenced by its correlation with genetic risk groups and TMB., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. author is an Editorial Board Member/Editor-in-Chief/Associate Editor/Guest Editor for this journal and was not involved in the editorial review or the decision to publish this article. CP and UKei received financial support for an investigator-initiated trial in mUM patients (EudraCT-Number: 2014–002439–32) from Sirtex and PharmaCept (now Magle PharmaCept). UKei is an Editorial Board Member for this journal and was not involved in the editorial review or the decision to publish this article. SO received financial compensation from Immunocore for participating in advisory boards. The other authors declare that they have no competing financial interests., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims: The MAPK pathway is constitutively activated in uveal melanoma (UM). Selumetinib (AZD6244, ARRY-142886), a MEK inhibitor, has shown limited activity as monotherapy in metastatic UM. Pre-clinical studies support synergistic cytotoxic activity for MEK inhibitors combined with taxanes, and here we sought to assess the clinical efficacy of combining selumetinib and paclitaxel., Patients and Methods: Seventy-seven patients with metastatic UM who had not received prior chemotherapy were randomised to selumetinib alone, or combined with paclitaxel with or without interruption in selumetinib two days before paclitaxel. The primary endpoint was progression free survival (PFS). After amendment, the combination arms were combined for analysis and the sample size adjusted to detect a hazard ratio (HR): 0.55, 80% power at 1-sided 5% significance level., Results: The median PFS in the combination arms was 4.8 months (95% CI: 3.8 - 5.6) compared with 3.4 months (2.0 - 3.9) in the selumetinib arm (HR 0.62 [90% CI 0.41 - 0.92], 1-sided p-value = 0.022). ORR was 14% and 4% in the combination and monotherapy arms respectively. Median OS was 9 months for the combination and was not significantly different from selumetinib alone (10 months) with HR of 0.98 [90% CI 0.58 - 1.66], 1-sided p-value = 0.469. Toxicity was in keeping with the known profiles of the agents involved., Conclusions: SelPac met its primary endpoint, demonstrating an improvement in PFS for combination selumetinib and paclitaxel. No improvement in OS was observed, and the modest improvement in PFS is not practice changing., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. JJS reports institutional funding for trial delivery from Amgen, AstraZeneca, Bristol-Myers Squibb, Delcath Systems, Merck, Replimune, Transgene; research grants from AstraZeneca, Bristol-Myers Squibb, Immunocore; paint consultancy/advisory Board membership from Bristol-Myers Squibb, Delcath Systems, Immunocore, Merck; and sponsorship for congress attendance: Bristol-Myers Squibb, Merck. TRJE has received honoraria for consultancies (payable to the employing institution) from Ascelia, Astra Zeneca, Bayer, Bicycle Therapeutics, Bristol-Myers Squibb, Celgene, Eisai, Karus Therapeutics, Medivir, MSD, Otsuka, Roche, and Seagen; honoraria for speaker’s fees (payable to employing institution) from Astra Zeneca, Ascelia, Bayer, Bristol Myers Squibb, Celgene, Eisai, Nucana, MSD, Roche, Medivir, and United Medical; has received support of costs of commercial clinical trials (payable to employing institution) from Astra Zeneca, Basilea, Bayer, Celgene, Exscientia; Exelexis; MiNa Therapeutics, Roche, Pfizer, Sierra, Lilly, Eisai, GSK, Novartis, Bicycle Therapeutics, Johnson and Johnson, CytomX, Vertex, Plexxikon, Boehringer, Athinex, Adaptimmune, Bristol Myers Squibb, MSD, Medivir, Versatem, Nucana, Immunocore, Berg, Beigene, Iovance, Modulate, BiolinerX, Merck Serono, Nurix Therapeutics, T3P, Janssen Clovis, Sanofi-Aventis, Halozyme, Starpharma, UCB, Sapience, Seagen, Avacta, and Codiak; has received funding from Cancer Research UK, Chief Scientist’s Office Scotland, and the MRC; (payable to employing institution); has received support to attend national & international congresses from Bristol-Myers Squibb, Roche, MSD, Celgene, Pierre-Fabre (personal). SO reports honoraria from BMS. Merck, MSD, AstraZeneca and Janssen; and consulting fees from MSD, Immuncore, Janssen and Genmab. JL reports research funding from Achilles, BMS, MSD, Nektar, Novartis, Pfizer, Roche, Immunocore, Aveo, Pharmacyclics; Consulting fees from iOnctura, Apple Tree, Merck, BMS, Eisai, Debipharm, Incyte; and Honoraria from Eisai, Novartis, Incyte, Merck, touchIME, touchEXPERTS, Pfizer, Royal College of Physicians, Cambridge Healthcare Research, Royal College of General Practitioners, VJOncology, Agence Unik, BMSIK reports consulting fees from Merck Serono; and research funding from Genetech, Achilles Therapeutics and Replimune. PL reports honoraria from Norvartis, PierreFabre, Merck , BMS, NeraCare GmbH, Amgen, Roche and oncology Education Canada; and research funding from BMS, PierreFabre. RP report honoraria for attending advisory boards from Pierre Faber, Bayer, Novartis, BMS, Ellipses, Immunocore, Genmab, Astex Therapeutics, MSD, Nerviano, AmLo, Incyte, Cybrexa Benevolent AI and Sanofi Aventis; honoraria for working as an IDMC member for Alligator Biosciences, GSK, Onxeo, SOTIO Biotech AG, and AstraZeneca; honoraria for delivery of educational talks or chairing educational meetings by AstraZeneca, Novartis, Bayer, MSD and BMS; and funds to support attendance at conferences from MSD and BMS. PP reports research funding from AstraZeneca. AO-B reports honoraria from BMS, MSD, Eisai, Roche, Novartis, AZ; and research Funding from BMS UCB pharma, Roche, Novartis and Eli Lily. HS report paid consultancy for Novartis, BMS, MSD, Immunocore, Idera, Iovance, Genmab, Sanofi Genzyme/Regeneron, Macrogenics, Roche, Agenus, Ideaya, iOnctura, CDR-Life, NovalGen, Therakos/Mallinkrodt Pharmaceuticals, ScanCelll; and speakers bureau for Novartis, BMS, MSD, Sanofi Genzyme/Regeneron, AstraZeneca, Eisai. SL reports consulting for Bayer, Immunocore; and expenses from Bayer. PN discloses Data and Safety Monitoring for 4SC, Achilles; and Consultant/Advisory Board for 4SC, Bristol-Myers Squibb, Immunocore, Merck, Merck Sharp and Dohme, Novartis, Pfizer; Research Grant/Contract: Immunocore. The other authors do not report any potential conflicting interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The impact of tumour mutational burden (TMB) on outcome with molecularly matched therapy is unknown. Higher TMB could predict resistance to molecularly matched therapy through co-occurring driver mutations., Methods: One hundred and four patients with advanced cancers underwent molecular profiling in the DKTK-MASTER program. Fifty-five patients received systemic therapy excluding immunotherapy. Patients with molecularly matched (n = 35) or non-molecularly informed therapy (n = 20) were analysed for TMB and survival. Results were validated in an independent cohort of patients receiving molecularly matched (n = 68) or non-molecularly informed therapy (n = 40). Co-occurring driver mutations and TMB were analysed in the exploratory cohort and The Cancer Genome Atlas (TCGA) datasets., Results: Patients were stratified by the median TMB of 1.67 mutations per Megabase (mut/Mb) of 35 patients receiving molecularly matched therapy into TMB-high or TMB-low groups. Median overall survival (4 months [95% CI, 3.3-7.6] versus 12.8 months [95% CI, 10-not reached], p < 0.001) and progression-free survival (1.8 months [95% CI, 1.1-3.7] versus 7.9 months [95% CI, 2.8-17.0], p = 0.003) were significantly shorter in the TMB-high group compared to the TMB-low group. In the validation cohort, shorter OS and PFS were identified in the TMB-high group (TMB cut-off of 4 mut/Mb) treated with molecularly matched therapy. No differences were observed in patients receiving non-molecularly informed systemic therapy. A significant correlation between co-occurring driver mutations and TMB (n = 104, r = 0.78 [95% CI, 0.68-0.85], p < 0.001) was found in the exploratory cohort as well as the majority (24/33) of TCGA studies., Conclusion: A high TMB was associated with unfavourable outcome in patients receiving molecularly matched therapy, indicating untargeted resistance pathways. Therefore, TMB should be further investigated as a predictive biomarker in precision oncology programs., Competing Interests: Declaration of Competing Interest Till de Bortoli, Manuela Benary, Mario Lamping, Reinhold Schäfer and Frederick Klauschen report no potential conflicts of interest. Peter Horak reported consulting or advisory board membership for Platomics and honoraria from Platomics, Roche. Sebastian Stintzing has received honoraria/consulting or advisory role from Amgen, Bayer, Lilly, Merck KGaA, MSD, Pierre Fabre, Roche, Sanofi, Servier, Taiho Pharmaceuticals, Takeda, Boehringer Ingelheim, research funding from Merck Serono, Pierre Fabre, Roche Molecular Diagnostics, travel, accommodation and expenses support from Amgen, Bayer, Lilly, Merck KgaA, Pierre Fabre, Roche, Sanofi, Sirtex Medical and Takeda. Inge Tinhofer reports honoraria/consulting or advisory role for Merck KgaA and MerckSerono. Serge Leyvraz reports consulting or advisory role and travel expenses support from Bayer. Ulrich Keller reports a consulting role for Roche, Janssen-Cilag, Takeda, BMS, Gilead, Hexal, Pfizer, Astra-Zeneca, Pentixapharm and honoraria from Gilead, Amgen, Novartis, BMS, Roche, Takeda, MSD, as well as research funding from Celgene, Takeda, BMS, Roche, Astra-Zeneka, Novartis, MSD, Janssen-Cilag, Pfizer. Other support was declared from Roche, BMS, Gilead, Takeda, Janssen-Cilag and Celgene. Albrecht Stenzinger reported Advisory Board/Speaker’s Bureau from Aignostics, Astra Zeneca, AGCT, Bayer, BMS, Eli Lilly, Illumina, Incyte, Janssen, MSD, Novartis, Pfizer, Roche, Seattle Genetics, Takeda, Thermo Fisher and research grants from Bayer, BMS, Chugai, Incyte. Stefan Fröhling reported consulting or advisory board membership from Bayer, Illumina, Roche; honoraria: Amgen, Eli Lilly, PharmaMar, Roche and research funding from AstraZeneca, Pfizer, PharmaMar, Roche, as well as travel or accommodation expenses support from Amgen, Eli Lilly, Illumina, PharmaMar, Roche. Razelle Kurzrock has received research funding from Biological Dynamics, Boehringer Ingelheim, Debiopharm, Foundation Medicine, Genentech, Grifols, Guardant, Incyte, Konica Minolta, Medimmune, Merck Serono, Omniseq, Pfizer, Sequenom, Takeda, and TopAlliance; as well as consultant and/or speaker fees and/or advisory board for Actuate Therapeutics, AstraZeneca, Bicara Therapeutics, Biological Dynamics, EISAI, EOM Pharmaceuticals, Iylon, Merck, NeoGenomics, Neomed, Pfizer, Prosperdtx, Roche, TD2/Volastra, Turning Point Therapeutics, X-Biotech and has an equity interest in CureMatch Inc., CureMetrix, and IDbyDNA; She also serves on the Board of CureMatch and CureMetrix,and is a co-founder of CureMatch. Ulrich Keilholz has received advisory board/speaker bureau, trial support, research collaboration or research support from Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Glycotope, Innate, Lilly, Medimmune, MerckSerono, MSD/Merck, Novartis, Pfizer, Roche/Genentech and Sirtex. Damian Rieke has received consultant and/or advisory board and/or speaker fees from Bayer, Bristol-Myers Squibb and Lilly. Ivan Jelas has received consultant and/or advisory board and/or speaker fees from Bristol-Myers Squibb, Merck and Roche., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Targeted therapies for metastatic uveal melanoma have shown limited benefit in biomarker-unselected populations. The Treat20 Plus study prospectively evaluated the feasibility of a precision oncology strategy in routine clinical practice., Patients and Methods: Fresh biopsies were analyzed by high-throughput genomics (whole-genome, whole-exome, and RNA sequencing). A multidisciplinary molecular and immunologic tumor board (MiTB) made individualized treatment recommendations based on identified molecular aberrations, patient situation, drug, and clinical trial availability. Therapy selection was at the discretion of the treating physician. The primary endpoint was the feasibility of the precision oncology clinical program., Results: Molecular analyses were available for 39/45 patients (87%). The MiTB provided treatment recommendations for 40/45 patients (89%), of whom 27/45 (60%) received ≥1 matched therapy. First-line matched therapies included MEK inhibitors (n = 15), MET inhibitors (n = 10), sorafenib (n = 1), and nivolumab (n = 1). The best response to first-line matched therapy was partial response in one patient (nivolumab based on tumor mutational burden), mixed response in two patients, and stable disease in 12 patients for a clinical benefit of 56%. The matched therapy population had a median progression-free survival and overall survival of 3.3 and 13.9 months, respectively. The growth modulation index with matched therapy was >1.33 in 6/17 patients (35%) with prior systemic therapy, suggesting clinical benefit., Conclusions: A precision oncology approach was feasible for patients with metastatic uveal melanoma, with 60% receiving a therapy matched to identify molecular aberrations. The clinical benefit after checkpoint inhibitors highlights the value of tumor mutational burden testing., Competing Interests: Conflict of interest statement SL reports travel and advisory board support from Immunocore and Bayer. CP reports speaker honoraria from Bristol-Myers Squibb, Novartis, Daiichi-Sankyo, EUSA Pharma and Sirtex Medical and advisory honoraria from EUSA Pharma. MS is employee of Alacris Theranostics. TK is employee of Alacris Theranostics. SO reports consultancy fees from Astra Zeneca, Bristol-Myers Squibb, Janssen Biotech, Merck. DTR reports Honoraria from Lilly, Bristol-Myers Squibb and Advisory Honoraria from Bayer and Alacris Theranostics. KK reports advisory board and conference honoraria from Merck, Sanofi, Merck Sharp & Dohme, Glycotope, Roche, Novartis and Bristol-Myers Squibb. CU reports consulting fees from Sanofi, grant for educational activities form Galderma, Beiresdorf and Almirall. GP reports consulting fees and grant for educational activities from Amgen. Novartis, Sun Pharma. Bristol-Myers Squibb, Merck Sharp & Dohme. FK is co-founder of Aignostics GmbH and has received consulting support from Roche, Novartis, Bristol-Myers Squibb, Lilly, Agilent and Iomedico. AJ reports Consultant fees from Novartis, Roche, Boehringer, Allergan, Bayer. MLY is an employee and shareholder of Alacris Theranostics. UK reports consulting fees for Merck Sharp & Dohme, travel support from Merck Serono, Pfizer, grant for educational activities from Merck Serono, Bristol-Myers Squibb, Pierre-Fabre. FK, MD, ES, GD, ML, SB, RS have no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Reliable and reproducible interpretation of molecular aberrations constitutes a bottleneck of precision medicine. Evidence-based decision management systems may improve rational therapy recommendations. To cope with an increasing amount of complex molecular data in the clinical care of patients with cancer, we established a workflow for the interpretation of molecular analyses., Methods: A specialized physician screened results from molecular analyses for potential biomarkers, irrespective of the diagnostic modality. Best available evidence was retrieved and categorized through establishment of an in-house database and interrogation of publicly available databases. Annotated biomarkers were ranked using predefined evidence levels and subsequently discussed at a molecular tumour board (MTB), which generated treatment recommendations. Subsequent translation into patient treatment and clinical outcomes were followed up., Results: One hundred patients were discussed in the MTB between January 2016 and May 2017. Molecular data were obtained for 70 of 100 patients (50 whole exome/RNA sequencing, 18 panel sequencing, 2 immunohistochemistry (IHC)/microsatellite instability analysis). The MTB generated a median of two treatment recommendations each for 63 patients. Thirty-nine patients were treated: 6 partial responses and 12 stable diseases were achieved as best responses. Genetic counselling for germline events was recommended for seven patients., Conclusion: The development of an evidence-based workflow allowed for the clinical interpretation of complex molecular data and facilitated the translation of personalized treatment strategies into routine clinical care. The high number of treatment recommendations in patients with comprehensive genomic data and promising responses in patients treated with combination therapy warrant larger clinical studies., Competing Interests: Conflict of interest statement M.L., M.B., C.M., E.B., K.J., S.B., K.K., S.O., R.S., and F.K. reported no conflicts of interest. S.L. received support and consulting compensation from Bayer. M.L.Y., T.K. and M.S. are employees of Alacris Theranostics. D.L. is currently an employee of AstraZeneca and reported employment, stock ownership and patents/royalties/intellectual property for her spouse at Bayer. C.S. received honoraria from Merck Serono, I.T. took part in an advisory board by Merck Serono. D.B. is a shareholder of MicroDiscovery GmbH. U.K. reported research funding from Merck Sharp & Dohme, Novartis, Bristol-Myers Squibb, Roche, GlaxoSmithKline, AstraZeneca and Merck Serono and served as a consultant or as a member of the advisory board with Merck Sharp & Dohme, Bristol-Myers Squibb, AstraZeneca, Merck Serono and GlaxoSmithKline. D.T.R. received payments as a consultant for Alacris Theranostics and honoraria from Bristol-Myers Squibb., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The past three decades have seen rapid improvements in the diagnosis and treatment of most cancers and the most important contributor has been research. Progress in rare cancers has been slower, not least because of the challenges of undertaking research., Settings: The International Rare Cancers Initiative (IRCI) is a partnership which aims to stimulate and facilitate the development of international clinical trials for patients with rare cancers. It is focused on interventional--usually randomized--clinical trials with the clear goal of improving outcomes for patients. The key challenges are organisational and methodological. A multi-disciplinary workshop to review the methods used in ICRI portfolio trials was held in Amsterdam in September 2013. Other as-yet unrealised methods were also discussed., Results: The IRCI trials are each presented to exemplify possible approaches to designing credible trials in rare cancers. Researchers may consider these for use in future trials and understand the choices made for each design., Interpretation: Trials can be designed using a wide array of possibilities. There is no 'one size fits all' solution. In order to make progress in the rare diseases, decisions to change practice will have to be based on less direct evidence from clinical trials than in more common diseases., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Patients diagnosed with advanced gastrointestinal stromal tumours (GISTs) who are resistant or intolerant to both imatinib and second-line sunitinib have a poor prognosis and few therapeutic options. We evaluated the efficacy of nilotinib, a novel tyrosine kinase inhibitor (TKI) in patients pretreated with imatinib and sunitinib. Fifty-two consecutive patients treated with oral nilotinib, 400mg twice daily, within the nilotinib compassionate use programme in 12 European cancer centres, were included in this retrospective analysis. Median age was 59 years (range 24-80), and all patients had WHO performance score better than 3. All patients had failed both imatinib and sunitinib pretreatment, either due to progressing GIST (96%) or intolerance (4%). Five patients (10%; 95% confidence interval (CI) 2-18) responded to nilotinib and 19 patients (37%; 95% CI 24-50) achieved a disease stabilisation. Nilotinib was generally well tolerated, but six patients (12%) discontinued treatment due to intolerance. Median progression-free survival of nilotinib treatment was 12 weeks (95% CI 9-15; range 0-104) and median overall survival was 34 weeks (95% CI 3-65; range 2-135). Nilotinib is active in GIST resistant to both imatinib and sunitinib. These results warrant further investigation of nilotinib in GIST.

A recent randomized EORTC phase III trial, comparing two doses of imatinib in patients with advanced gastrointestinal stromal tumours (GISTs), reported dose dependency for progression-free survival. The current analysis of that study aimed to assess if tumour mutational status correlates with clinical response to imatinib. Pre-treatment samples of GISTs from 377 patients enrolled in phase III study were analyzed for mutations of KIT or PDGFRA by combination of D-HPLC and direct sequencing of tumour genomic DNA. Mutation types were correlated with patients' survival data. The presence of exon 9-activating mutations in KIT was the strongest adverse prognostic factor for response to imatinib, increasing the relative risk of progression by 171% (P<0.0001) and the relative risk of death by 190% (P<0.0001) when compared with KIT exon 11 mutants. Similarly, the relative risk of progression was increased by 108% (P<0.0001) and the relative risk of death by 76% (P=0.028) in patients without detectable KIT or PDGFRA mutations. In patients whose tumours expressed an exon 9 KIT oncoprotein, treatment with the high-dose regimen resulted in a significantly superior progression-free survival (P=0.0013), with a reduction of the relative risk of 61%. We conclude that tumour genotype is of major prognostic significance for progression-free survival and overall survival in patients treated with imatinib for advanced GISTs. Our findings suggest the need for differential treatment of patients with GISTs, with KIT exon 9 mutant patients benefiting the most from the 800 mg daily dose of the drug.

Temozolomide, an oral imidazotetrazine derivative, was given to 31 patients with advanced soft tissue sarcoma. The dose of 750 mg/m2 was divided over 5 consecutive days, and escalated to 1000 mg/m2 over 5 days at cycle 2 if myelosuppression no worse than common toxicity criteria grade 2 was noted in the first 28-day cycle. A total of 99 treatment cycles were given to 31 patients. The drug was well tolerated, with nausea and vomiting as the most common side-effects. Only one partial tumour response was documented, giving a response rate of 3.33%, 95% confidence interval, (CI) 0.1-17.2%. The median time to progression was 8 weeks and the median survival was 27 weeks. These results indicate that temozolomide in this schedule is not active as second-line treatment in advanced soft tissue sarcoma.

The prognosis of stage III non-small cell lung cancer (NSCLC) can be improved by a combination of radiotherapy (RT) and chemotherapy (CT). In this study, the GOTHA group evaluated the feasibility, tolerance, tumour response, pattern of failure and effect on survival of a combination alternating accelerated hyperfractionated (AH) RT and CT in patients with tumour stage III NSCLC. 65 patients received 3 cycles of cisplatin 60 mg/m2 and mitomycin C 8 mg/m2 on day 1, and vindesin 3 mg/m2 on days 1 and 8 in weeks 1-2, 5-6 and 9-10, alternating with AHRT, 2 daily 1.5 Gy fractions, 5 days/week, in weeks 2-3 (30 Gy) and weeks 6-7 (33 Gy). The dose actually delivered was > 98% for RT, and 85-100% for CT. Mean duration before last CT cycle was 9.5 weeks. Toxic effects were leucopenia, nausea and vomiting, mucositis, diarrhoea, alopecia and peripheral neuropathy. 1 patient died of bronchial haemorrhage at the end of RT. 1 of 5 patients, who underwent secondary pulmonary resections, died of acute respiratory distress syndrome. Evaluation of tumour response was hampered by lung condensations in radiation fields. Some long-term survivors had an initial tumour response assessed as partial response or no change. First failures were more frequent outside (34) than within (21) radiation fields. The median survival was 15.7 months and the 5 year survival rate was 15% (95% CI = 6-26%). 1 patient died of bladder cancer and another of myocardial infarction. Alternating CT and AHRT, as used in this study, were well tolerated and allowed full dose delivery within less than 12 weeks. Initial response was not predictive of survival. The survival curve is encouraging and the 5 year survival is superior to the 5% generally observed with conventionally fractionated radiotherapy.

Little progress has been made in the systemic treatment of melanoma, that is for disseminated stage IV disease. However, the tumour resistance to therapy, especially chemotherapy can be overcome in melanoma by high doses of anticancer agents administered regionally. The purpose of this paper is to illustrate this concept by two modes of regional treatment namely: (1) isolation perfusion of the limbs with high doses of cytokines and chemotherapy under hyperthermia and (2) local treatment of metastatic melanoma. The third part will be devoted to the role of another regional treatment, radiotherapy, where the association with hyperthermy also looks promising.

We report the results and discuss the toxicity of clinical trials based on a single concept: the decrease in O6alkyl DNA alkyltransferase (O6AT) resistance mechanism when a chloroethylating agent is used sequentially after a methylating agent. This decrease in O6AT being dose dependent, several increasing doses of dacarbazine (DTIC) have been tested (400 mg/m2 to 1000 mg/m2 every 4 weeks, 3-4 h before fotemustine (100 mg/m2 intravenously every 4 weeks). These results (mean overall response rate 27%) compared with reference regimes, demonstrate that DTIC is able to increase the alkylating power of fotemustine: same range of response rate with only half of the two drug doses compared to an alternated combination, high activity rate especially in lung metastases (10/42 complete responses + 13/42 partial responses), different pattern for haematotoxicity, and occurrence of a new side-effect: acute lung toxicity as adult respiratory distress syndrome (ARDS). This lung toxicity was totally unexpected since several hundreds of patients had been so far treated with fotemustine as single agent or in other combinations with DTIC without any case of acute or delayed lung toxicity. Prophylactic administration of corticoids was not effective and monitoring of the respiratory function was of no predictive value. Due to the additional depleting effects of DTIC on at least two main defence mechanisms--the O6AT system and cytosolic and/or nuclear glutathione--we suppose that the sequence is able to increase the alkylating power of fotemustine to an excessive extent and/or that the detoxication capacity of the cell against DTIC and/or fotemustine metabolites is overwhelmed. Other depletors of the O6AT activity which do not generate metabolites that compete for the same detoxication pathway as the chloroethylnitrosourea (CENU) metabolites should be tested.

28 patients with progressing painful bone metastases (18 breast cancer, 9 myeloma and 1 low grade lymphoma) received pamidronate 60 mg by 24 h continuous infusion for at least 2 courses (range 2-12). In patients urinary calcium and hydroxyproline excretion significantly decreased in relation to diminution of bone resorption. 9 of 18 breast cancer patients and 8 of 9 evaluable patients with myeloma had symptomatic improvement. Sclerotic areas of previously lytic lesions appeared in 8 breast cancer patients and in 1 myeloma patient. Transient fever developed in 1 patient and local phlebitis in 2. Among the 28 patients, 15 did not receive any anticancer treatment or have any change of the anticancer therapy during pamidronate administration. Of 7 with breast cancer, 4 had an improvement of symptoms and 4 sclerosis on radiographs. Impressive control of symptoms was the major feature of 8 myeloma patients, but only 1 had radiographic sclerosis.