Volker Budach

CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment ☆

Multiple systems have been developed for grading the adverse effects (AEs) of cancer treatment. The National Cancer Institute Common Toxicity Criteria (CTC) system has substantially evolved since its inception in 1983. The most recent version, CTCAE v3.0 (Common Terminology Criteria for Adverse Events version 3.0) represents the first comprehensive, multimodality grading system for reporting the acute and late effects of cancer treatment. The new CTC requires changes in the application of AE criteria including new guidelines regarding late effects, surgical and pediatric effects, multimodality issues, and for reporting the duration of an effect. It builds on the strengths of previous systems, represents a considerable effort among hundreds of participants, and signifies an international collaboration and consensus of the oncology research community. This article updates recent progress in the evolution of adverse effects grading systems and reviews the development of CTCAE v3.0.

Internal Mammary and Medial Supraclavicular Irradiation in Breast Cancer

BACKGROUND The effect of internal mammary and medial supraclavicular lymph-node irradiation (regional nodal irradiation) added to whole-breast or thoracic-wall irradiation after surgery on survival among women with early-stage breast cancer is unknown. METHODS We randomly assigned women who had a centrally or medially located primary tumor, irrespective of axillary involvement, or an externally located tumor with axillary involvement to undergo either whole-breast or thoracic-wall irradiation in addition to regional nodal irradiation (nodal-irradiation group) or whole-breast or thoracic-wall irradiation alone (control group). The primary end point was overall survival. Secondary end points were the rates of disease-free survival, survival free from distant disease, and death from breast cancer. RESULTS Between 1996 and 2004, a total of 4004 patients underwent randomization. The majority of patients (76.1%) underwent breast-conserving surgery. After mastectomy, 73.4% of the patients in both groups underwent chest-wall irradiation. Nearly all patients with node-positive disease (99.0%) and 66.3% of patients with node-negative disease received adjuvant systemic treatment. At a median follow-up of 10.9 years, 811 patients had died. At 10 years, overall survival was 82.3% in the nodal-irradiation group and 80.7% in the control group (hazard ratio for death with nodal irradiation, 0.87; 95% confidence interval [CI], 0.76 to 1.00; P=0.06). The rate of disease-free survival was 72.1% in the nodal-irradiation group and 69.1% in the control group (hazard ratio for disease progression or death, 0.89; 95% CI, 0.80 to 1.00; P=0.04), the rate of distant disease-free survival was 78.0% versus 75.0% (hazard ratio, 0.86; 95% CI, 0.76 to 0.98; P=0.02), and breast-cancer mortality was 12.5% versus 14.4% (hazard ratio, 0.82; 95% CI, 0.70 to 0.97; P=0.02). Acute side effects of regional nodal irradiation were modest. CONCLUSIONS In patients with early-stage breast cancer, irradiation of the regional nodes had a marginal effect on overall survival. Disease-free survival and distant disease-free survival were improved, and breast-cancer mortality was reduced. (Funded by Fonds Cancer; ClinicalTrials.gov number, NCT00002851.).

Hyperfractionated Accelerated Chemoradiation With Concurrent Fluorouracil-Mitomycin Is More Effective Than Dose-Escalated Hyperfractionated Accelerated Radiation Therapy Alone in Locally Advanced Head and Neck Cancer: Final Results of the Radiotherapy Cooperative Clinical Trials Group of the German Cancer Society 95-06 Prospective Randomized Trial

PURPOSE To report the results and corresponding acute and late reactions of a prospective, randomized, clinical study in locally advanced head and neck cancer comparing concurrent fluorouracil (FU) and mitomycin (MMC) chemotherapy and hyperfractionated accelerated radiation therapy (C-HART; 70.6 Gy) to hyperfractionated accelerated radiation therapy alone (HART; 77.6 Gy). PATIENTS AND METHODS Three hundred eighty-four stage III (6%) and IV (94%) oropharyngeal (59.4%), hypopharyngeal (32.3%), and oral cavity (8.3%) cancer patients were randomly assigned to receive either 30 Gy (2 Gy every day) followed by 1.4 Gy bid to a total of 70.6 Gy concurrently with FU (600 mg/m(2), 120 hours continuous infusion) days 1 through 5 and MMC (10 mg/m(2)) on days 5 and 36 (C-HART) or 14 Gy (2 Gy every day) followed by 1.4 Gy bid to a total dose of 77.6 Gy (HART). The data were analyzed on an intent-to-treat basis. RESULTS At 5 years, the locoregional control and overall survival rates were 49.9% and 28.6% for C-HART versus 37.4% and 23.7% for HART, respectively (P = .001 and P = .023, respectively). Progression-free and freedom from metastases rates were 29.3% and 51.9% for C-HART versus 26.6% and 54.7% for HART, respectively (P = .009 and P = .575, respectively). For C-HART, maximum acute reactions of mucositis, moist desquamation, and erythema were lower than with HART, whereas no differences in late reactions and overall rates of secondary neoplasms were observed. CONCLUSION C-HART (70.6 Gy) is superior to dose-escalated HART (77.6 Gy) with comparable or less acute reactions and equivalent late reactions, indicating an improvement of the therapeutic ratio.

A meta-analysis of hyperfractionated and accelerated radiotherapy and combined chemotherapy and radiotherapy regimens in unresected locally advanced squamous cell carcinoma of the head and neck

BackgroundFormer meta-analyses have shown a survival benefit for the addition of chemotherapy (CHX) to radiotherapy (RT) and to some extent also for the use of hyperfractionated radiation therapy (HFRT) and accelerated radiation therapy (AFRT) in locally advanced squamous cell carcinoma (SCC) of the head and neck. However, the publication of new studies and the fact that many older studies that were included in these former meta-analyses used obsolete radiation doses, CHX schedules or study designs prompted us to carry out a new analysis using strict inclusion criteria.MethodsRandomised trials testing curatively intended RT (≥60 Gy in >4 weeks/>50 Gy in <4 weeks) on SCC of the oral cavity, oropharynx, hypopharynx, and larynx published as full paper or in abstract form between 1975 and 2003 were eligible. Trials comparing RT alone with concurrent or alternating chemoradiation (5-fluorouracil (5-FU), cisplatin, carboplatin, mitomycin C) were analyzed according to the employed radiation schedule and the used CHX regimen. Studies comparing conventionally fractionated radiotherapy (CFRT) with either HFRT or AFRT without CHX were separately examined. End point of the meta-analysis was overall survival.ResultsThirty-two trials with a total of 10 225 patients were included into the meta-analysis. An overall survival benefit of 12.0 months was observed for the addition of simultaneous CHX to either CFRT or HFRT/AFRT (p < 0.001). Separate analyses by cytostatic drug indicate a prolongation of survival of 24.0 months, 16.8 months, 6.7 months, and 4.0 months, respectively, for the simultaneous administration of 5-FU, cisplatin-based, carboplatin-based, and mitomycin C-based CHX to RT (each p < 0.01). Whereas no significant gain in overall survival was observed for AFRT in comparison to CFRT, a substantial prolongation of median survival (14.2 months, p < 0.001) was seen for HFRT compared to CFRT (both without CHX).ConclusionRT combined with simultaneous 5-FU, cisplatin, carboplatin, and mitomycin C as single drug or combinations of 5-FU with one of the other drugs results in a large survival advantage irrespective the employed radiation schedule. If radiation therapy is used as single modality, hyperfractionation leads to a significant improvement of overall survival. Accelerated radiation therapy alone, especially when given as split course radiation schedule or extremely accelerated treatments with decreased total dose, does not increase overall survival.

Remineralisation und Schmerzlinderung von Knochenmetastasen nach unterschiedlich fraktionierter Strahlentherapie (10mal 3 Gy vs. 1mal 8 Gy)Eine prospektive Studie

Hintergrund: Es wurde eine prospektive randomisierte Studie zur Bestrahlung von Knochenmetastasen durchgeführt, die sowohl die Schmerzansprechrate als auch die Remineralisation als Kriterien des Therapieerfolgs berücksichtigte. Patienten und Methode: 107 Patienten mit histologisch gesichertem Mamma-, Bronchial-, Prostata- und Nierenzellkarzinom, die eine schmerzhafte und röntgenologisch sichtbare Osteolyse hatten, wurden in die Studie aufgenommen. Es erfolgten eine Stratifizierung nach den Entitäten und eine Randomisation in zwei unterschiedliche Therapiearme (10mal 3 Gy vs 1mal 8 Gy). Die Erfassung der Schmerzansprechrate erfolgte mit Hilfe eines Schmerz- und Schmerzmittel-Scores und der subjektiven Einschätzung der Patienten. Die Remineralisation wurde am Computertomographen gemessen. Sowohl die Schmerzreduktion als auch die Remineralisation wurden vor, unmittelbar nach der Therapie sowie sechs Wochen, drei und sechs Monate nach Bestrahlungsabschluß erfaßt. Ergebnisse: Bei der Schmerzreduktion ergab sich im Vergleich beider Therapiearme sowohl hinsichtlich der Gesamtansprechrate (81% vs. 78%) als auch der kompletten Schmerzreduktion (33% vs. 31%) kein Unterschied. Im 1mal-8-Gy-Arm wurde ein etwas rascheres Ansprechen auf die Therapie beobachtet. Bei der Remineralisation ergab sich ein hochsignifikanter Unterschied (p < 0,0001) im Vergleich aller Patienten zugunsten des fraktionierten Therapiearms (173% vs. 120%). Im fraktionierten Arm zeigte sich ein signifikanter Unterschied zwischen Mamma- und Bronchialkarzinomen (p = 0,015). Dieser Unterschied wurde im Vergleichsarm (1mal 8 Gy) nicht gesehen. Beim Vergleich der unterschiedlichen Therapiearme hinsichtlich der einzelnen Tumorentitäten zeigte sich zwar bei allen eine Tendenz zugunsten des fraktionierten Therapiearmes, ein signifkanter Unterschied wurde nur beim Mammakarzinom gemessen (p < 0,001). Schlußfolgerung: Schmerzreduktion und Remineralisation liegen unterschiedliche Wirkungsmechanismen zugrunde. Bei alleiniger Berücksichtigung der Schmerzen ist ein Kurzzeitschema zu empfehlen, da es effektiv und wenig belastend für den Patienten ist. Unter Berücksichtigung der Remineralisation ist einem fraktionierten Schema der Vorzug zu geben, da hiermit eine größere biologische Wirksamkeit erzielt wird und damit die Grundlage für eine bessere Stabilisierung gegeben ist.Background: In a prospective randomized trial we examined pain relief and recalcification following radiotherapy for bone metastases. Patients and Methods: One hundred and seven patients with histologically proven breast, lung, prostate or kidney cancer and radiologically confirmed bone metastases were included in this trial. They were stratified to primary tumor sites and randomized in 2 different fractionation schedules: 1 × 8 Gy vs 10 × 3 Gy. Pain relief was registered using of pain score, analgesic usage and subjective perception of pain. The recalcification was measured at the computertomograph. Pain status and recalcification were assessed before, day after, 6 weeks, 3 and 6 months after radiotherapy. Results: There was no significant difference in overall (81% vs 78%) and complete (33% vs 31%) pain response. In the single dose group (1 × 8 Gy) the pain response was measured a little rarer. The recalcification showed a significant difference between patients in the fractionated group (173%) and the single dose group (120%, p < 0.0001). In the fractionated group there was a significant difference between patients with breast and lung cancer (p = 0.015). There was a slight trend favoring 10 × 3 Gy in recalcification for all primary tumor sites but only a significant difference in breast cancer (p < 0.001). Conclusion: The basis of pain response and recalcification is different. In mere consideration of pain a short-course fractionation is recommendable. This fractionation schedule is effective, well tolerable and short. In consideration of recalcification a more fractionated schedule is recommendable because the biological efficacy is higher and this leads to better stabilisation.

Prophylactic Cranial Irradiation in Locally Advanced Non–Small-Cell Lung Cancer After Multimodality Treatment: Long-Term Follow-Up and Investigations of Late Neuropsychologic Effects

PURPOSE Relapse pattern and late toxicities in long-term survivors were analyzed after the introduction of prophylactic cranial irradiation (PCI) into a phase II trial on trimodality treatment of locally advanced (LAD) non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Seventy-five patients with stage IIIA(N2)/IIIB NSCLC were treated with induction chemotherapy, preoperative radiochemotherapy, and surgery. PCI was routinely offered during the second period of study accrual. Patients were given a total radiation dose of 30 Gy (2 Gy per daily fraction) over a 3-week period starting 1 day after the last chemotherapy cycle. RESULTS Introduction of PCI reduced the rate of brain metastases as first site of relapse from 30% to 8% at 4 years (P =.005) and that of overall brain relapse from 54% to 13% (P <.0001). The effect of PCI was also observed in the good-prognosis subgroup of 47 patients who had a partial response or complete response to induction chemotherapy, with a reduction of brain relapse as first failure from 23% to 0% at 4 years (P =.01). Neuropsychologic testing revealed impairments in attention and visual memory in long-term survivors who received PCI as well as in those who did not receive PCI. T2-weighted magnetic resonance imaging revealed white matter abnormalities of higher grades in patients who received PCI than in those who did not. CONCLUSION PCI at a moderate dose reduced brain metastases in LAD-NSCLC to a clinically significant extent, comparable to that in limited-disease small-cell lung cancer. Late toxicity to normal brain was acceptable. This study supports the use of PCI within intense protocols for LAD-NSCLC, particularly in patients with favorable prognostic factors.

Commissioning of a micro multi-leaf collimator and planning system for stereotactic radiosurgery

PURPOSE A computer controlled micro multi-leaf collimator, m3 mMLC, has been commissioned for conformal, fixed-field radiosurgery applications. Measurements were made to characterise the basic dosimetric properties of the m3, such as leaf transmission, leakage and beam penumbra. In addition, the geometric and dosimetric accuracy of the m3 was verified when used in conjunction with a BrainSCAN v3.5 stereotactic planning system. MATERIALS AND METHODS The m3 was detachably mounted to a Varian Clinac 2100C accelerator delivering 6 MV X-rays. Leaf transmission, leakage, penumbra and multiple, conformal fixed field dose distributions were measured using calibrated film in solid water. Beam data were collected using a diamond detector in a scanning water tank and planned dose distributions were verified using LiF TLDs and film. A small, shaped phantom was also constructed to confirm field shaping accuracy using portal images. RESULTS Mean transmission through the closed multi-leaves was 1.9 +/- 0.1% and leakage between leaves was 2.8 +/- 0.15%. Between opposing leaves abutting along the central beam-axis transmission was approximately 15 +/- 3%, but was reduced to a mean of 4.5 +/- 0.6% by moving the abutmen position 4.5 cm off-axis. Beam penumbrae were effectively constant as a function of increasing square field size and asymmetric fields and was seen to vary non-linearly when shaped to diagonal, straight edges. TMR, OAR and relative output beam data measurements of circular m3 fields were comparable to conventional, circular stereotactic collimators. Multiple, conformal field dose distributions were calculated with good spatial and dosimetric accuracy, with the planned 90% isodose curves agreeing with measurements to within 1-2 mm and to +/- 3% at isocentre. Portal films agreed with planned beams eye-view field shaping to within 1 mm. CONCLUSIONS The m3 micro multi-leaf collimator is a stable, high precision field-shaping device suitable for small-field, radiosurgery applications. Dose distributions can be accurately calculated by a planning system using only a few beam data parameters.

IMPACT OF THE FILLING STATUS OF THE BLADDER AND RECTUM ON THEIR INTEGRAL DOSE DISTRIBUTION AND THE MOVEMENT OF THE UTERUS IN THE TREATMENT PLANNING OF GYNAECOLOGICAL CANCER

PURPOSE Determination of the impact of the filling status of the organs at risk (bladder and rectum) on the uterus mobility and on their integral dose distribution in radiotherapy of gynaecological cancer. METHODS In 29 women suffering from cervical or endometrial cancer two CT scans were carried out for treatment planning, one with an empty bladder and rectum, the second one with bladder and rectum filled. The volumes of the organs at risk were calculated and in 14 patients, receiving a definitive radiotherapy, the position of the uterus within the pelvis was shown using multiplanar reconstructions. After generation of a 3D treatment plan the dose volume histograms were compared for empty and filled organs at risk. RESULTS The mobility for the corpus uteri with/without bladder and rectum filling was in median 7 mm (95%-confidence interval: 3-15 mm) in cranial/caudal direction and 4 mm (0-9 mm) in posterior/anterior direction. Likewise, cervical mobility was observed to be 4 mm (-1-6 mm) mm in cranial/caudal direction. A full bladder led to a mean reduction in organ dose in median from 94-87% calculated for 50% of the bladder volume (P < 0.05, Wilcoxons matched-pairs signed-ranks test). For 66% of the bladder volume the dose could be reduced in median from 78 to 61% (P < 0.005) and for the whole bladder from 42 to 39% (P < 0.005), respectively. No significant contribution of the filling status of the rectum to its integral dose burden was noticed. CONCLUSIONS Due to the mobility of the uterus increased margins between CTV and PTV superiorly, inferiorly, anteriorly and posteriorly of 15, 6 and 9 mm each, respectively, should be used. A full bladder is the prerequisite for an integral dose reduction.

Image guided respiratory gated hypofractionated Stereotactic Body Radiation Therapy (H-SBRT) for liver and lung tumors: Initial experience

To evaluate our initial experience with image guided respiratory gated H-SBRT for liver and lung tumors. The system combines a stereoscopic x-ray imaging system (ExacTrac® X-Ray 6D) with a dedicated conformal stereotactic radiosurgery and radiotherapy linear accelerator (Novalis) and ExacTrac® Adaptive Gating for dynamic adaptive treatment. Moving targets are located and tracked by x-ray imaging of implanted fiducial markers defined in the treatment planning computed tomography (CT). The marker position is compared with the position in verification stereoscopic x-ray images, using fully automated marker detection software. The required shift for a correct, gated set-up is calculated and automatically applied. We present our acceptance testing and initial experience in patients with liver and lung tumors. For treatment planning CT and Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) as well as magnetic resonance imaging (MRI) taken at free breathing and expiration breath hold with internal and external fiducials present were used. Patients were treated with 8–11 consecutive fractions to a dose of 74.8–79.2 Gy. Phantom tests demonstrated targeting accuracy with a moving target to within ±1 mm. Inter- and intrafractional patient set-up displacements, as corrected by the gated set-up and not detectable by a conventional set-up, were up to 30 mm. Verification imaging to determine target location during treatment showed an average marker position deviation from the expected position of up to 4 mm on real patients. This initial evaluation shows the accuracy of the system and feasibility of image guided real-time respiratory gated H-SBRT for liver and lung tumors.

Final results of the randomized phase III CHARTWEL-trial (ARO 97-1) comparing hyperfractionated-accelerated versus conventionally fractionated radiotherapy in non-small cell lung cancer (NSCLC)

BACKGROUND Continuous hyperfractionated accelerated radiotherapy (CHART) counteracts repopulation and may significantly improve outcome of patients with non-small-cell lung cancer (NSCLC). Nevertheless high local failure rates call for radiation dose escalation. We report here the final results of the multicentric CHARTWEL trial (CHART weekend less, ARO 97-1). PATIENTS AND METHODS Four hundred and six patients with NSCLC were stratified according to stage, histology, neoadjuvant chemotherapy and centre and were randomized to receive 3D-planned radiotherapy to 60Gy/40 fractions/2.5weeks (CHARTWEL) or 66Gy/33 fractions/6.5weeks (conventional fractionation, CF). RESULTS Overall survival (OS, primary endpoint) at 2, 3 and 5yr was not significantly different after CHARTWEL (31%, 22% and 11%) versus CF (32%, 18% and 7%; HR 0.92, 95% CI 0.75-1.13, p=0.43). Also local tumour control rates and distant metastases did not significantly differ. Acute dysphagia and radiological pneumonitis were more pronounced after CHARTWEL, without differences in clinical signs of pneumopathy. Exploratory analysis revealed a significant trend for improved LC after CHARTWEL versus CF with increasing UICC, T or N stage (p=0.006-0.025) and after neoadjuvant chemotherapy (HR 0.48, 0.26-0.89, p=0.019). CONCLUSIONS Overall, outcome after CHARTWEL or CF was not different. The lower total dose in the CHARTWEL arm was compensated by the shorter overall treatment time, confirming a time factor for NSCLC. The higher efficacy of CHARTWEL versus CF in advanced stages and after chemotherapy provides a basis for further trials on treatment intensification for locally advanced NSCLC.