W. Budach

Radiation induced CNS toxicity: molecular and cellular mechanisms

Radiotherapy of tumours proximal to normal CNS structures is limited by the sensitivity of the normal tissue. Prior to the development of prophylactic strategies or treatment protocols a detailed understanding of the mechanisms of radiation induced CNS toxicity is mandatory. Histological analysis of irradiated CNS specimens defines possible target structures prior to a delineation of cellular and molecular mechanisms. Several lesions can be distinguished: Demyelination, proliferative and degenerative glial reactions, endothelial cell loss and capillary occlusion. All changes are likely to result from complex alterations within several functional CNS compartments. Thus, a single mechanism responsible cannot be separated. At least four factors contribute to the development of CNS toxicity: (1) damage to vessel structures; (2) deletion of oligodendrocyte-2 astrocyte progenitors (O-2A) and mature oligodendrocytes; (3) deletion of neural stem cell populations in the hippocampus, cerebellum and cortex; (4) generalized alterations of cytokine expression. Several underlying cellular and molecular mechanisms involved in radiation induced CNS toxicity have been identified. The article reviews the currently available data on the cellular and molecular basis of radiation induced CNS side effects.

Neoadjuvant capecitabine combined with standard radiotherapy in patients with locally advanced rectal cancer: mature results of a phase II trial.

Purpose:The objective of this expanded phase II trial was to confirm the safety results of the preceding phase I study and establish the efficacy of neoadjuvant radiochemotherapy with capecitabine in rectal cancer in a multicenter setting.Patients and Methods:96 patients (63% male, age 34–81 years) with advanced rectal cancer (cT3–4 or cN+) from seven university centers in Germany were recruited. All were to receive a total irradiation dose of 50.4–55.8 Gy with conventional fractions. Capecitabine was given at an oral dosage of 825 mg/m2bid on each day of the radiotherapy period with the first daily dose applied 2 h before irradiation, followed by surgery 6 weeks later.Results:Most of the patients suffered from an advanced primary tumor (cT3: 57%, cT4: 40%) with lymph node involvement in 60%. After neoadjuvant treatment, with a mean of 99% of the scheduled radiation dose actually delivered, a clinical response rate of 68% (95% confidence interval: 57–78%) was observed. Out of 87 evaluable patients undergoing surgery, a sphincter-preserving procedure could be performed in 51% and R0 resection in 94%. A pathologically complete response was achieved in six patients (7%, 95% confidence interval: 3–14%). The comparison of initial diagnosis and pathologic findings showed a downstaging in 61%. Acute toxicity with > 5% incidence of NCI (National Cancer Institute) grade ≥ 3 included lymphopenia (12%), leukopenia (6%), and diarrhea (7%). Mild to moderate hand-foot syndrome occurred in 12% only. After a median follow-up of 48 months, the 5-year overall survival and tumor control data were, with regard to patient selection, in the expected range with an overall survival of 65%, a relapse-free survival of 47%, and a local recurrence rate after 5 years of 17%.Conclusion:The data clearly confirm that capecitabine is an adequate substitute for 5-fluorouracil in preoperative chemoradiation of rectal cancer with a favorable safety profile.Ziel:Diese multizentrische Phase-II-Studie sollte Effektivität und Toxizität einer neoadjuvanten Radiochemotherapie mit Capecitabine prüfen.Patienten und Methodik:96 Patienten (davon 63% männlich, Alter 34–81 Jahre) mit lokal fortgeschrittenem Rektumkarzinom (cT3–4 oder cN+) aus sieben deutschen Universitätskliniken wurden rekrutiert. Alle erhielten eine präoperative Radiotherapie (50,4–55,8 Gy in konventioneller Fraktionierung mit 5 × 1,8 Gy) und zusätzlich 2 × täglich 825 mg/m2Capecitabin während gesamten Radiotherapie (erste Dosis 2 h vor Radiotherapie, keine Pause am Wochenende). 6 Wochen nach der Radiochemotherapie war die Resektion geplant.Ergebnisse:97% der Patienten hatten T3/T4-Tumoren (T3: 57%; T4: 40%). Lymphknotenbefall (cN+) lag in 60% vor. Die präoperative Therapie war gut durchführbar (mittlere Strahlendosis 99%, mittlere Capecitabindosis 96% der geplanten Dosis). Die klinische Ansprechrate betrug 68% (95%-Konfidenzintervall: 57–78%) und entsprach der Studienhypothese. Von 87 auswertbaren operierten Patienten wurden 94% R0-reseziert; ein Sphinktererhalt war in 51% möglich. Sechs Patienten (7%, 95%-Konfidenzintervall: 3–14%) hatten eine histologisch komplette Remission (ypT0) im Resektat. Ein Downstaging wurde in 61% erreicht. Akute Nebenwirkungen CTC-Grad ≥ 3 (Common Toxicity Criteria) mit einer Frequenz von > 5% wurden für Lymphopenie (12%), Diarrhö (7%) und Leukopenie (6%) beobachtet. Ein Hand-Fuß-Syndrom trat in 12% auf und war jeweils nur mild (Grad 1–2). Die 5-Jahres-Überlebensrate betrug 65%, das rezidivfreie Überleben 47% und die lokale Kontrolle nach 5 Jahren 83%.Schlussfolgerung:Die Daten dieser multizentrischen Phase-II-Studie bestätigen, dass die Kombination von präoperativer Radiotherapie und Capecitabin eine wirksame und nebenwirkungsarme Behandlung beim lokal fortgeschrittenen Rektumkarzinom darstellt. Capecitabin eignet sich als Ersatz für eine kontinuierliche 5-Fluorouracil-Infusion.

Neoadjuvant Capecitabine Combined with Standard Radiotherapy in Patients with Locally Advanced Rectal Cancer

Purpose:The objective of this expanded phase II trial was to confirm the safety results of the preceding phase I study and establish the efficacy of neoadjuvant radiochemotherapy with capecitabine in rectal cancer in a multicenter setting.Patients and Methods:96 patients (63% male, age 34–81 years) with advanced rectal cancer (cT3–4 or cN+) from seven university centers in Germany were recruited. All were to receive a total irradiation dose of 50.4–55.8 Gy with conventional fractions. Capecitabine was given at an oral dosage of 825 mg/m2bid on each day of the radiotherapy period with the first daily dose applied 2 h before irradiation, followed by surgery 6 weeks later.Results:Most of the patients suffered from an advanced primary tumor (cT3: 57%, cT4: 40%) with lymph node involvement in 60%. After neoadjuvant treatment, with a mean of 99% of the scheduled radiation dose actually delivered, a clinical response rate of 68% (95% confidence interval: 57–78%) was observed. Out of 87 evaluable patients undergoing surgery, a sphincter-preserving procedure could be performed in 51% and R0 resection in 94%. A pathologically complete response was achieved in six patients (7%, 95% confidence interval: 3–14%). The comparison of initial diagnosis and pathologic findings showed a downstaging in 61%. Acute toxicity with > 5% incidence of NCI (National Cancer Institute) grade ≥ 3 included lymphopenia (12%), leukopenia (6%), and diarrhea (7%). Mild to moderate hand-foot syndrome occurred in 12% only. After a median follow-up of 48 months, the 5-year overall survival and tumor control data were, with regard to patient selection, in the expected range with an overall survival of 65%, a relapse-free survival of 47%, and a local recurrence rate after 5 years of 17%.Conclusion:The data clearly confirm that capecitabine is an adequate substitute for 5-fluorouracil in preoperative chemoradiation of rectal cancer with a favorable safety profile.Ziel:Diese multizentrische Phase-II-Studie sollte Effektivität und Toxizität einer neoadjuvanten Radiochemotherapie mit Capecitabine prüfen.Patienten und Methodik:96 Patienten (davon 63% männlich, Alter 34–81 Jahre) mit lokal fortgeschrittenem Rektumkarzinom (cT3–4 oder cN+) aus sieben deutschen Universitätskliniken wurden rekrutiert. Alle erhielten eine präoperative Radiotherapie (50,4–55,8 Gy in konventioneller Fraktionierung mit 5 × 1,8 Gy) und zusätzlich 2 × täglich 825 mg/m2Capecitabin während gesamten Radiotherapie (erste Dosis 2 h vor Radiotherapie, keine Pause am Wochenende). 6 Wochen nach der Radiochemotherapie war die Resektion geplant.Ergebnisse:97% der Patienten hatten T3/T4-Tumoren (T3: 57%; T4: 40%). Lymphknotenbefall (cN+) lag in 60% vor. Die präoperative Therapie war gut durchführbar (mittlere Strahlendosis 99%, mittlere Capecitabindosis 96% der geplanten Dosis). Die klinische Ansprechrate betrug 68% (95%-Konfidenzintervall: 57–78%) und entsprach der Studienhypothese. Von 87 auswertbaren operierten Patienten wurden 94% R0-reseziert; ein Sphinktererhalt war in 51% möglich. Sechs Patienten (7%, 95%-Konfidenzintervall: 3–14%) hatten eine histologisch komplette Remission (ypT0) im Resektat. Ein Downstaging wurde in 61% erreicht. Akute Nebenwirkungen CTC-Grad ≥ 3 (Common Toxicity Criteria) mit einer Frequenz von > 5% wurden für Lymphopenie (12%), Diarrhö (7%) und Leukopenie (6%) beobachtet. Ein Hand-Fuß-Syndrom trat in 12% auf und war jeweils nur mild (Grad 1–2). Die 5-Jahres-Überlebensrate betrug 65%, das rezidivfreie Überleben 47% und die lokale Kontrolle nach 5 Jahren 83%.Schlussfolgerung:Die Daten dieser multizentrischen Phase-II-Studie bestätigen, dass die Kombination von präoperativer Radiotherapie und Capecitabin eine wirksame und nebenwirkungsarme Behandlung beim lokal fortgeschrittenen Rektumkarzinom darstellt. Capecitabin eignet sich als Ersatz für eine kontinuierliche 5-Fluorouracil-Infusion.

Radiotherapy and concomitant weekly 1-hour infusion of paclitaxel in the treatment of head and neck cancer—Results from a phase I trial

PURPOSE To define the maximum tolerated dose (MTD) by describing the dose-limiting toxicity (DLT) of weekly paclitaxel (PAC) given as a 1-h I.V. infusion in patients with head and neck cancer concomitant to irradiation. METHODS AND MATERIALS Patients with unresectable or incompletely resected head and neck cancer were enrolled into a prospective, dose-escalating Phase I study. Toxicity was graded according to the WHO toxicity score. MTD dose was defined when two out of six patients developed DLT. The starting dose of PAC was 20 mg/m2 once weekly I.V. over 60 min, with a subsequent dose escalation of 10 mg/m2 in cohorts of three new patients. Radiation therapy was administered in three field technique over 6-7 weeks in 2.0 Gy/daily fractions for 5 consecutive days/week up to total doses of 60-70 Gy. RESULTS From 1994-1996, 18 patients completing three dose levels were included into the study. Altogether, 101 courses of chemotherapy were evaluable for toxicity. On the second dose level (30 mg/m2) one of three patients experienced DLT with Grade IV mucositis. On the next dose level with 40 mg/m2 PAC weekly one patient experienced DLT being prolonged Grade III mucositis. From the following three patients required, two patients showed no DLT. The third patient showed mucositis of WHO Grade 4 and died from hemorrhage caused by a rupture of the a pharyngeal wall. Dose level 2 (30 mg/m2) was repeated and one of the three newly treated patients again suffered from mucositis WHO Grade 4. CONCLUSION When PAC is given weekly as a 1-h infusion concomitant to radiotherapy, MTD is 30 mg/m2 with mucositis being DLT; hematological and further nonhematological toxicity is mild.

Local recurrences of soft tissue sarcomas in adults: a restrospective analysis of prognostic factors in 102 cases after surgery and radiation therapy

Between 1974 and 1990, 102 adult patients (age 18-86 years) with the diagnosis of a soft tissue sarcoma (STS) were treated with photons and/or electrons in combination with surgery. The total doses in the initial treatment volume (second order target volume) was 40-50 Gy. For the coning down volume (first order target volume) the median total dose was 59 Gy (range 45-72 Gy). A total of 18% (18/102) local failures was observed. In multivariate analysis, prognostic factors for the occurrence of a local failure were identified as follows: treatment of a primary or recurrent STS (P = 0.02), total dose (P = 0.025) and tumour grade (P = 0.05). Mode of surgery, tumour size (trunk versus extremity), pre- or postoperative radiotherapy, combined chemotherapy and tumour size (T1 versus T2) had no significant impact on the local relapse-free survival. These data give further evidence that combined surgery and radiotherapy is an effective modality in treatment of soft tissue sarcomas.

Mitomycin C in combination with radiotherapy as a potent inhibitor of tumour cell repopulation in a human squamous cell carcinoma.

The potential of Mitomycin C in combination with fractionated irradiation to inhibit tumour cell repopulation of a fast growing squamous cell carcinoma after fractionated radiotherapy was investigated in vivo. A rapidly growing human squamous cell carcinoma (FaDudd) was used for the study. For experiments, NMRI (nu/nu) mice with subcutaneously growing tumours were randomly allocated to no treatment, Mitomycin C, fractionated irradiation (ambient: 11x4.5 Gy in 15 days), or fractionated irradiation combined with Mitomycin C. Graded top up doses (clamped blood flow: 0–57 Gy) were given at day 16, 23, 30 or 37. End point of the study was the time to local tumour progression. Data were examined by multiple regression analysis (Cox). Mitomycin C alone resulted in a median time to local tumour progression of 23 (95% confidence limits: 17–43) days, fractionated irradiation in 31 (25–35) days and combined Mitomycin C plus fractionated irradiation in 65 (58–73) days (P=0.02). Mitomycin C decreased the relative risk of local recurrence by 94% (P<<0.001) equivalent to 31.7 Gy top up dose. Repopulation accounted for 1.33 (0.95–1.72) Gy per day top up dose after fractionated irradiation alone and for 0.68 (0.13–1.22) Gy per day after fractionated irradiation+Mitomycin C (P=0.018). Mitomycin C significantly reduces the risk of local recurrence and inhibits tumour cell repopulation in combination with fractionated irradiation in vivo in the tested tumour model.

Molecular requirements for the combined effects of TRAIL and ionising radiation.

BACKGROUND AND PURPOSE Previously it was shown that combination of death ligand TRAIL and irradiation strongly increases cell kill in several human tumour cell lines. Since Bcl-2 overexpression did not strongly interfere with the efficacy, components of the mitochondrial death pathway are not required for an effective combined treatment. In the present study the minimal molecular prerequisites for the efficacy of a combined treatment were determined. MATERIALS AND METHODS Apoptosis induction in control, caspase-8 and FADD negative Jurkat cells, BJAB control and FADD-DN cells was analysed by FACS. Activation of caspase-8, -10 and -3 and cleavage of PARP was determined by immunoblotting. TRAIL receptors were activated using recombinant human TRAIL. Surface expression of TRAIL receptors DR4 and DR5 was analysed by FACS. RESULTS Jurkat T-cells express the agonistic DR5 receptor but not DR4. Presence of FADD was found to be essential for TRAIL induced apoptosis. Caspase-8 negative cells show very low rates of apoptosis after prolonged stimulation with TRAIL. No combined effects of TRAIL with irradiation could be found in FADD-DN overexpressing and FADD deficient cells. However, the combination of TRAIL and irradiation clearly lead to a combined effect in caspase-8 negative Jurkat cells, albeit with reduced death rates. In these cells activation of the alternative initiator caspase-10 could be detected after combined treatment. CONCLUSION Our data show that a combined therapy with TRAIL and irradiation will only be effective in cells expressing at least one agonistic TRAIL receptor, FADD and caspase-8 or caspase-10.

Thermoradiotherapy for locally recurrent breast cancer with skin involvement

Purpose: This retrospective analysis investigated the effectiveness and side-effects of combined hyperthermia and radiation therapy in locally recurrent breast cancer after primary modified radical mastectomy. The aim of the thermoradiotherapy was to reduce the substantial risk of symptomatic chest wall disease. Materials and methods: Between May 1995-August 1998, 39 extensively pre-treated women with progressive locoregional chest wall tumours were treated with local radiofrequency hyperthermia, given twice a week immediately before radiotherapy. Sixty-two per cent of the patients had received previous radiotherapy, with a median dose of 50Gy, 64% had received chemotherapy, 36% hormonal therapy, and 13% local therapy with miltefosin, respectively. Nine patients were treated for microscopic residual disease after local tumour excision (R1-resection) and 30 patients for gross macroscopic nodular recurrences. Twenty-seven patients had two adjacent hyperthermia fields at the ipsilateral chest wall to cover the whole irradiation area. Each field received a median of seven local hyperthermia sessions (range 2-12, average 5.6 sessions) just before radiation therapy, with a median dose of 60Gy (range 30-68Gy). The monitored maximumaverage and averageaverage epicutaneous temperatures were 42.1°C and 41.0°C, respectively. Maximumaverage and averageaverage intratumoural temperatures of 43.0°C and 41.1°C, respectively, were achieved in nine chest wall recurrences with intratumoural temperature probes. Concurrent hormonal therapy was administered in 48%, and concurrent chemotherapy in 10% of patients. Results: Median overall survival time was 28 months (Kaplan Meier), with 71% and 54% of patients living 1 and 2 years after thermoradiotherapy. The median time to local failure has not been reached, local tumour control after 2 years being 53%. Actuarial 1 and 2 year local tumour controls for microscopic residual disease were 89%, and for macroscopic nodular recurrences 71% and 46%, respectively (p = 0.09). Actuarial 1 and 2 year local tumour controls after treatment with a total dose of less than 60Gy were 51% and 38%, respectively, and, after a total dose greater than 60Gy, 84% and 60% (p = 0.01), respectively. Actuarial 1 year local tumour control was 92% after complete tumour remission, versus 57% after partial remission (p = 0.002). Three of the 39 patients died of cancer en cuirasse, 13 patients due to distant metastases. Acute thermoradiotherapy related erythema, dry desquamation and moist desquamation were seen in 28.2%, 30.7%, and 30.7% of patients, respectively. Soft tissue necrosis occurred in two patients with previous post-operative delayed wound healing, and in one patient above a silicon implant. Conclusion: This study showed that, in extensively pre-treated patients with locally recurrent breast cancer, local tumour control after thermoradiotherapy depended on tumour resectability, response of macroscopic tumour to thermoradiotherapy, and total irradiation dose.PURPOSE This retrospective analysis investigated the effectiveness and side-effects of combined hyperthermia and radiation therapy in locally recurrent breast cancer after primary modified radical mastectomy. The aim of the thermoradiotherapy was to reduce the substantial risk of symptomatic chest wall disease. MATERIALS AND METHODS Between May 1995-August 1998, 39 extensively pre-treated women with progressive locoregional chest wall tumours were treated with local radiofrequency hyperthermia, given twice a week immediately before radiotherapy. Sixty-two per cent of the patients had received previous radiotherapy, with a median dose of 50 Gy, 64% had received chemotherapy, 36% hormonal therapy, and 13% local therapy with miltefosin, respectively. Nine patients were treated for microscopic residual disease after local tumour excision (R1-resection) and 30 patients for gross macroscopic nodular recurrences. Twenty-seven patients had two adjacent hyperthermia fields at the ipsilateral chest wall to cover the whole irradiation area. Each field received a median of seven local hyperthermia sessions (range 2-12, average 5.6 sessions) just before radiation therapy, with a median dose of 60 Gy (range 30-68 Gy). The monitored maximum(average) and average(average) epicutaneous temperatures were 42.1 degrees C and 41.0 degrees C, respectively. Maximum(average) and average(average) intratumoural temperatures of 43.0 degrees C and 41.1 degrees C, respectively, were achieved in nine chest wall recurrences with intratumoural temperature probes. Concurrent hormonal therapy was administered in 48%, and concurrent chemotherapy in 10% of patients. RESULTS Median overall survival time was 28 months (Kaplan Meier), with 71% and 54% of patients living 1 and 2 years after thermoradiotherapy. The median time to local failure has not been reached, local tumour control after 2 years being 53%. Actuarial 1 and 2 year local tumour controls for microscopic residual disease were 89%, and for macroscopic nodular recurrences 71% and 46%, respectively (p = 0.09). Actuarial 1 and 2 year local tumour controls after treatment with a total dose of less than 60 Gy were 51% and 38%, respectively, and, after a total dose greater than 60 Gy, 84% and 60% (p = 0.01), respectively. Actuarial 1 year local tumour control was 92% after complete tumour remission, versus 57% after partial remission (p = 0.002). Three of the 39 patients died of cancer en cuirasse, 13 patients due to distant metastases. Acute thermoradiotherapy related erythema, dry desquamation and moist desquamation were seen in 28.2%, 30.7%, and 30.7% of patients, respectively. Soft tissue necrosis occurred in two patients with previous post-operative delayed wound healing, and in one patient above a silicon implant. CONCLUSION This study showed that, in extensively pre-treated patients with locally recurrent breast cancer, local tumour control after thermoradiotherapy depended on tumour resectability, response of macroscopic tumour to thermoradiotherapy, and total irradiation dose.

Current and Potential Role of Thermoradiotherapy for Solid Tumours

The disappointing results for inoperable, locally advanced or recurrent solid tumours of the uterine cervix, rectum, chest wall, liver and deep seated, high-risk sarcomas after conventional radiotherapy alone necessitate the search for improved treatments. A benefit from simultaneous radiochemotherapy with regard to local tumour control and survival has been shown for a rising number of tumour entities. Radiofrequency hyperthermia is established in only a few centres, and represents another option to intensify the effect of radio- and chemotherapy. Altogether 11 randomised phase III trials with more than 1,000 patients proved the combination of hyperthermia (40–42 °C for at least 1 h) and radiation therapy in reference to local tumour control. Two of these trials could demonstrate a survival benefit; e.g. in locally advanced cervical cancer, stage FIGO IIB–IVa, the 3-year survival was improved from 27 to 51% with the addition of hyperthermia. Frequently trial design (main endpoint local tumour control), a low number of patients or a short follow- up period are the reasons why most trials of thermoradiotherapy failed to demonstrate a survival benefit. Disadvantageous effects of hyperthermia like an increased rate of distant metastases as a result of hyperthermia-induced elevated perfusion can be largely ruled out. While at the moment the equivalence of thermoradiotherapy and radiochemotherapy is still under evaluation, future studies have to investigate the question whether hyperthermia can add benefits when used in combination with simultaneous radiochemotherapy. An ongoing investigation of hyperthermia in multimodal treatment strategies for locally advanced solid tumours is warranted. These trials will help to improve temperature monitoring and temperature distribution and define particular groups of patients who will profit from the addition of hyperthermia. The ‘Interdisziplinäre Arbeitsgruppe Hyperthermie’, a working group of the German Cancer Society, introduces clinical protocols, treatment devices, and provides information for patients at www.hyperthermie.org.

Neoadjuvant chemoradiotherapy of stage III non-small-cell lung cancer

Twenty to 30% of patients with non-small-cell lung cancer (NSCLC) in stage III are not resectable primarily with 5-year survival less than 10%. Since the majority of patients die from metastases, efforts have been made in the past to improve prognosis by application of neoadjuvant chemoradiotherapy regimens followed by subsequent resection. In a phase II study performed between 1993 and 1998, 93 patients in stage III (IIIA, 16%; IIIB, 84%) received an induction chemotherapy consisting of two cycles cisplatin (100 mg/m2) and vindesine (3 mg/m2) with subsequent sequential radiotherapy of 36 Gy. Sixty-five patients demonstrated partial or complete remission. Sixty underwent surgery; in 49 of them complete resection was possible. Five-year survival in the whole group was 24%, and that in the surgical cohort 39%. Six patients had no residual tumor. Postoperative N0 status was associated with a 5-year survival of 75%, and stage N1-3 with 13%. Thirty-day mortality was 7% postoperatively. Neoadjuvant chemoradiotherapy can significantly improve long-term survival in stage III NSCLC with an acceptable therapy-induced mortality.