Michael Flentje

Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy—results of a multicentric randomized German trial in advanced head-and-neck cancer

PURPOSE To demonstrate the efficacy of radiochemotherapy (RCT) as the first choice of treatment for advanced unresectable head-and-neck cancer. To prove an expected benefit of simultaneously given chemotherapy, a two-arm randomized study with hyperfractionated accelerated radiochemotherapy (HF-ACC-RCT) vs. hyperfractionated accelerated radiotherapy (HF-ACC-RT) was initiated. The primary endpoint was 1-year survival with local control (SLC). METHODS AND MATERIALS Patients with Stage III and IV (UICC) unresectable oro- and hypopharyngeal carcinomas were randomized for HF-ACC-RCT with 2 cycles of 5-FU (600 mg/m(2)/day)/carboplatinum (70 mg/m(2)) on days 1--5 and 29--33 (arm A) or HF-ACC-RT alone (arm B). In both arms, there was a second randomization for testing the effect of prophylactically given G-CSF (263 microg, days 15--19) on mucosal toxicity. Total RT dose in both arms was 69.9 Gy in 38 days, with a concomitant boost regimen (weeks 1--3: 1.8 Gy/day, weeks 4 and 5: b.i.d. RT with 1.8 Gy/1.5 Gy). Between July 1995 and May 1999, 263 patients were randomized (median age 56 years; 96% Stage IV tumors, 4% Stage III tumors). RESULTS This analysis is based on 240 patients: 113 patients with RCT and 127 patients with RT, qualified for protocol and starting treatment. There were 178 oropharyngeal and 62 hypopharyngeal carcinomas. Treatment was tolerable in both arms, with a higher mucosal toxicity after RCT. Restaging showed comparable nonsignificant different CR + PR rates of 92.4% after RCT and 87.9% after RT (p = 0.29). After a median observed time of 22.3 months, l- and 2-year local-regional control (LRC) rates were 69% and 51% after RCT and 58% and 45% after RT (p = 0.14). There was a significantly better 1-year SLC after RCT (58%) compared with RT (44%, p = 0.05). Patients with oropharyngeal carcinomas showed significantly better SLC after RCT (60%) vs. RT (40%, p = 0.01); the smaller group of hypopharyngeal carcinomas had no statistical benefit of RCT (p = 0.84). For both tumor locations, prophylactically given G-CSF was a poor prognostic factor (Cox regression), and resulted in reduced LRC (log-rank test: +/- G-CSF, p = 0.0072). CONCLUSION With accelerated radiotherapy, the efficiency of simultaneously given chemotherapy may be not as high as expected when compared to standard fractionated RT. Oropharyngeal carcinomas showed better LRC after HF-ACC-RCT vs. HF-ACC-RT; hypopharyngeal carcinomas did not. Prophylactic G-CSF resulted in an unexpected reduced local control and should be given in radiotherapy regimen only with strong hematologic indication.

Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: results of the german prospective randomized trial hit ’91

Purpose: The German Society of Pediatric Hematology and Oncology (GPOH) conducted a randomized, prospective, multicenter trial (HIT ’91) in order to improve the survival of children with medulloblastoma by using postoperative neoadjuvant chemotherapy before radiation therapy as opposed to maintenance chemotherapy after immediate postoperative radiotherapy. Methods and Materials: Between 1991 and 1997, 158 patients were enrolled and 137 patients randomized. Seventy-two patients were allocated to receive neoadjuvant chemotherapy before radiotherapy (arm I, investigational). Chemotherapy consisted of ifosfamide, etoposide, intravenous high-dose methotrexate, cisplatin, and cytarabine given in two cycles. In arm II (standard arm), 65 patients were assigned to receive immediate postoperative radiotherapy, with concomitant vincristine followed by 8 cycles of maintenance chemotherapy consisting of cisplatin, CCNU, and vincristine (“Philadelphia protocol”). All patients received radiotherapy to the craniospinal axis (35.2 Gy total dose, 1.6 Gy fractionated dose / 5 times per week followed by a boost to posterior fossa with 20 Gy, 2.0 Gy fractionated dose). Results: During chemotherapy Grade III/IV infections were predominant in arm I (40%). Peripheral neuropathy and ototoxicity were prevailing in arm II (37% and 34%, respectively). Dose modification was necessary in particular in arm II (63%). During radiotherapy acute toxicity was mild in the majority of patients and equally distributed in both arms. Myelosuppression led to a mean prolongation of treatment time of 11.5 days in arm I and 7.5 days in arm II, and interruptions in 35% of patients in arm I. Quality control of radiotherapy revealed correct treatment in more than 88% for dose prescription, more than 88% for coverage of target volume, and 98% for field matching. At a median follow-up of 30 months (range 1.4–62 months), the Kaplan-Meier estimates for relapse-free survival at 3 years for all randomized patients were 0.70 ± 0.08; for patients with residual disease: 0.72 ±0.06; without residual disease: 0.68 ± 0.09; M0: 0.72 ± 0.04; M1: 0.65 ± 0.12; and M2/3: 0.30 ± 0.15. For all randomized patients without M2/3 disease: 0.65± 0.05 (arm I) and 0.78 ± 0.06 (arm II) (p < 0.03); patients between 3 and 5.9 years: 0.60 ± 0.13 and 0.64 ± 0.14, respectively, but patients between 6 and 18 years: 0.62 ± 0.09 and 0.84 ± 0.08, respectively (p < 0.03). In a univariate analysis the only negative prognostic factors were M2/3 disease (p < 0.002) and an age of less than 8 years (p < 0.03). Conclusions: Maintenance chemotherapy would seem to be more effective in low-risk medulloblastoma, especially in patients older than 6 years of age. Neoadjuvant chemotherapy was accompanied by increased myelotoxicity of the subsequent radiotherapy, causing a higher rate of interruptions and an extended overall treatment time. Delayed and/or protracted radiotherapy may therefore have a negative impact on outcome. M2/3 disease was associated with a poor survival in both arms, suggesting the need for a more intensive treatment. Young age and M2/3 stage were negative prognostic factors in medulloblastoma, but residual or M1 disease was not, suggesting a new stratification system for risk subgroups. High quality of radiotherapy may be a major contributing factor for the overall outcome.

Stereotactic Radiotherapy of Targets in the Lung and Liver

Background: Stereotactic irradiation of extracranial targets offers a non-invasive treatment modality for patients with localized tumors, which are not amenable for surgery or other invasive approaches because of age or impaired medical condition. The purpose of the study was the evaluation of the method to achieve local control of irradiated targets in relation to treatment toxicity. Patients and Methods: Irradiation was performed as hyperfractionated treatment in three fractions of 10 Gy each, normalized to the PTV enclosing 65% isodose with patient fixation in a stereotactic body frame. The isocenter was localized by stereotactic coordinates. Targets were circumscribed tumors in the lung (n = 27) and liver (n = 24) not amenable for other treatment modalities: primary lung cancer (n = 12), local recurrences of lung cancer (n = 4), lung metastases (n = 11), liver metastases (n = 23) and one cholangiocellular carcinoma. Median CTV/PTV for targets in the lung was 57/113 cm3 (min/max 5–277 cm3/17–343 cm3) and for targets in the liver 50/102 cm3 (min/max 9–516 cm3/42–772 cm3). Median follow-up for targets in the lung was 8 months (2–33) and 9 months (2–28) for liver targets. Local control was defined as complete or partial remission and stable disease, measured by repeated CT scans after 6 weeks and in 3 months intervals. Treatment toxicity was evaluated according to the WHO score. Results: Crude local control was 85% for pulmonary targets and 83% for hepatic targets. Actuarial local control after 1 and 2 years was 76% and 76% for lung tumors and 76% and 61% for liver tumors. Actuarial overall patient survival was 48% after 1 year and 21% after 2 years for targets in the lung and 71% and 43% for targets in the liver. No acute grade 3–5 side effects were observed. Serious late toxicity occurred in two patients: a chronic ulceration of the esophagus at a target close to the mediastinum after 3 months (grade 3) and fatal bleeding from the pulmonary artery after 9 months (grade 5) in a previously irradiated patient. It remained unclear, whether the bleeding was a side effect of irradiation or due to tumor infiltration. Conclusion: Hypofractionated stereotactic irradiation of targets in the lung and liver is a locally effective treatment with actuarial local control rates of 76% after 1 year and 61–76% after 2 years without relevant acute toxicity. Severe late toxicity did not occur, if targets close to the mediastinum were avoided.Hintergrund: Prüfung eines hypofraktionierten, stereotaktischen Behandlungsansatzes für Bestrahlung lokalisierter Raumforderungen in der Lunge und Leber hinsichtlich lokaler Tumorkontrolle und Nebenwirkungen. Patienten und Methode: Stereotaktische Bestrahlung in drei Fraktionen à 10 Gy, normalisiert auf die PTV-umschließende 65%-Isodose mit Patientenfixierung im stereotaktischen Körperrahmen. Insgesamt wurden 27 Lungentumoren (zwölf primäre und vier lokoregionär rezidivierte Bronchialkarzinome, elf Metastasen) und 24 Lebertumoren (23 Metastasen, ein cholangiozelluläres Karzinom) behandelt. Das CTV/PTV für Lungenherde betrug im Median 57/113 cm3 (min/max 5–277 cm3/17–343 cm3), für Leberherde 50/102 cm3 (min/max 9–516 cm3/42–772 cm3). Die mediane Nachbeobachtungszeit betrug 8 Monate (2–33) für Lungen- und 9 Monate (2–28) für Leberherde. Lokale Kontrolle wurde definiert als computertomographisch komplette oder partielle Remission sowie Wachstumsstopp 6 Wochen sowie in Intervallen von 3 Monaten nach Therapie. Die Nebenwirkungen wurden nach WHO klassifiziert. Ergebnis: Lokale Kontrolle betrug numerisch in der Lunge 85%, in der Leber 83%, aktuarisch in der Lunge 76% nach 1 und 2 Jahren, in der Leber 76% nach 1 Jahr, 61% nach 2 Jahren. Das aktuarische Gesamtüberleben lag nach 1 und 2 Jahren bei Lungenherden bei 48% und 21% bzw. bei Leberherden bei 71% und 43%. Akut traten keine Nebenwirkungen Grad 3–5 auf. Als Spätnebenwirkung wurden eine chronische Ösophagitis (Grad 3) bei einem dicht am Mediastinum gelegenen Tumor sowie eine fatale Blutung aus der Arteria pulmonalis beobachtet, bei der jedoch auch eine tumorbedingte Arrosionsblutung nicht auszuschließen war. Schlussfolgerung: Die stereotaktische Bestrahlung von Lungen- und Leberherden ist eine effektive Bestrahlungsform mit aktuarischen lokalen Kontrollraten bis zu 76% nach 1 Jahr bzw. 61–76% nach 2 Jahren. Die Akuttoxizität war gering; schwere Spätnebenwirkungen traten nicht auf, wenn Zielvolumina in der Nähe des Mediastinums vermieden wurden.

Stereotactic radiotherapy of extracranial targets: CT-simulation and accuracy of treatment in the stereotactic body frame.

BACKGROUND AND PURPOSE Evaluation of set-up accuracy and analysis of target reproducibility in the stereotactic body frame (SBF), designed by Blomgren and Lax from Karolinska Hospital, Stockholm. Different types of targets were analyzed for the risk of target deviation. The correlation of target deviation to bony structures was analyzed to evaluate the value of bones as reference structures for isocenter verification. MATERIALS AND METHODS Thirty patients with 32 targets were treated in the SBF for primary or metastatic peripheral lung cancer, liver metastases, abdominal and pelvic tumor recurrences or bone metastases. Set-up accuracy and target mobility were evaluated by CT-simulation and port films. The contours of the target at isocenter level, bony structures and body outline were compared by matching the CT-slices for treatment planning and simulation using the stereotactic coordinates of the SBF as external reference system. The matching procedure was performed by using a 3D treatment planning program. RESULTS Set-up accuracy represented by bony structures revealed standard deviations (SD) of 3.5 mm in longitudinal, 2.2 mm in anterior-posterior and 3.9 mm in lateral directions. Target reproducibility showed a SD of 4.4 mm in longitudinal, 3.4 mm ap and 3.3 mm in lateral direction prior to correction. Correlation of target deviation to bones ranged from 33% (soft tissue targets) to 100% (bones). CONCLUSION A security margin of 5 mm for PTV definition is sufficient, if CT simulation is performed prior to each treatment to correct larger target deviations or set-up errors. Isocenter verification relative to bony structures is only safe for bony targets but not for soft tissue targets.

Stereotactic radiotherapy of primary liver cancer and hepatic metastases

The purpose was to evaluate the clinical results of stereotactic radiotherapy in primary liver tumors and hepatic metastases. Five patients with primary liver cancer and 39 patients with 51 hepatic metastases were treated by stereotactic radiotherapy since 1997. Twenty-eight targets were treated in a “low-dose”-group with 3×10 Gy (n = 27) or 4×7 Gy (n = 1) prescribed to the PTV-encl. 65%-isodose. In a “high-dose”-group patients were treated with 3×12 − 12.5 Gy (n = 19; same dose prescription) or 1×26 Gy/PTV-enclosing 80%-isodose (n = 9). Median follow-up was 15 months (2–48 months) for primary liver cancer and 15 months (2–85 months) for hepatic metastases. While all primary liver cancers were controlled, nine local failures (3–19 months) of 51 metastases were observed resulting in an actuarial local control rate of 92% after 12 months and 66% after 24 months and later. A borderline significant correlation between dose and local control was observed (p = 0.077): the actuarial local control rate after 12 and 24 months was 86% and 58% in the low-dose-group versus 100% and 82% in the high-dose-group. In multivariate analysis high versus low-dose was the only significant factor predicting local control (p = 0.0089). Overall survival after 1 and 2 years was 72% and 32% for all patients and was impaired due to systemic progression of disease. No severe acute or late toxicity exceeding RTOG/EORTC-score 2 were observed. Stereotactic irradiation of primary liver cancer and hepatic metastases offers a locally effective treatment without significant complications in patients, who are not amenable for surgery. Patient selection is important, because those with low risk for systemic progression are more likely to benefit from this approach.

Multicenter Phase II Trial of Chemoradiation With Oxaliplatin for Rectal Cancer

PURPOSE To evaluate the activity and safety of preoperative radiotherapy (RT) and concurrent capecitabine and oxaliplatin (XELOX-RT) plus four cycles of adjuvant XELOX in patients with rectal cancer. PATIENTS AND METHODS One hundred ten patients with T3/T4 or N+ rectal cancer were entered onto the trial in 11 investigator sites and received preoperative RT (50.4 Gy in 28 fractions). Capecitabine was administered concurrently at 1,650 mg/m2 on days 1 to 14 and 22 to 35, and oxaliplatin was administered at 50 mg/m2 on days 1, 8, 22, and 29. Surgery was scheduled 4 to 6 weeks after completion of XELOX-RT. Four cycles of adjuvant XELOX (capecitabine 1,000 mg/m2 bid on days 1 to 14; oxaliplatin 130 mg/m2 on day 1) were administered. The main end points were activity as assessed by the pathologic complete response (pCR) rate and the feasibility of postoperative XELOX chemotherapy. RESULTS After XELOX-RT, 103 of 104 eligible patients underwent surgery; pCR was achieved in 17 patients (16%), one patient had ypT0N1 disease, and 53 patients showed tumor regression of more than 50% of the tumor mass. R0 resections were achieved in 95% of patients, and sphincter preservation was accomplished in 77%. Full-dose preoperative XELOX-RT was administered in 96%. Grade 3 or 4 diarrhea occurred in 12% of patients. Postoperative complication occurred in 43% of patients. Sixty percent of patients received all four cycles of adjuvant XELOX, with sensory neuropathy (18%) and diarrhea (12%) being the main grade 3 or 4 toxicities. CONCLUSION Preoperative XELOX-RT plus four cycles of adjuvant XELOX is an active and feasible treatment. This regimen is proposed for phase III evaluation comparing standard fluorouracil-based treatment with XELOX- based multimodality treatment.

Inversion recovery TrueFISP: Quantification of T1, T2, and spin density

A novel procedure is proposed to extract T1, T2, and relative spin density from the signal time course sampled with a series of TrueFISP images after spin inversion. Generally, the recovery of the magnetization during continuous TrueFISP imaging can be described in good approximation by a three parameter monoexponential function S(t) = Sstst(1‐INV exp(‐t/T  *1 ). This apparent relaxation time T  *1 ≤ T1 depends on the flip angle as well as on both T1 and T2. Here, it is shown that the ratio T1/T2 can be directly extracted from the inversion factor INV, which describes the relation of the signal value extrapolated to t = 0 and the steady‐state signal. Analytical expressions are given for the derivation of T1, T2, and relative spin density directly from the fit parameters. Phantom results show excellent agreement with single point reference measurements. In human volunteers T1, T2, and spin density maps in agreement with literature values were obtained. Magn Reson Med 51:661–667, 2004.

Is a single arc sufficient in volumetric-modulated arc therapy (VMAT) for complex-shaped target volumes?

PURPOSE To compare step-and-shoot intensity-modulated radiotherapy (ss-IMRT) with volumetric-modulated arc therapy (VMAT) for complex-shaped target volumes with a simultaneous integrated boost (SIB). MATERIALS AND METHODS This retrospective planning study was based on 20 patients composed of prostate cancer (n=5), postoperative (n=5) or primary (n=5) radiotherapy for pharyngeal cancer and for cancer of the paranasal sinuses (n=5); a SIB with two or three dose levels was planned in all patients. For each patient, one ss-IMRT plan with direct-machine-parameter optimization (DMPO) and VMAT plans with one to three arcs (SmartArc technique) were generated in the Pinnacle planning system. RESULTS Single arc VMAT improved target coverage and dose homogeneity in radiotherapy for prostate cancer. Two and three VMAT arcs were required to achieve equivalent results compared to ss-IMRT in postoperative and primary radiotherapy for pharyngeal cancer, respectively. In radiotherapy for cancer of the paranasal sinuses, multiarc VMAT resulted in increased spread of low doses to the lenses and decreased target coverage in the region between the orbits. CONCLUSIONS The complexity of the target volume determined whether single arc VMAT was equivalent to ss-IMRT. Multiple arc VMAT improved results compared to single arc VMAT at cost of increased delivery times, increased monitor unites and increased spread of low doses.

Dose, volume, and tumor control prediction in primary radiotherapy of non-small-cell lung cancer.

BACKGROUND To evaluate the influence of total dose and tumor volume on local control and survival in primary radiotherapy of non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS We retrospectively analyzed the clinical course and CT-derived pre- and post-therapeutic tumor volume data of 135 patients with NSCLC undergoing primary radiotherapy at our department between 1989 and 1996. Among these, a total of 192 spatially separated tumor volumes (135 primary tumors, 1 additional intrapulmonary tumor, and 56 involved lymph nodes) were available for analysis. In all patients, treatment was planned using CT-based three-dimensional treatment planning. The dose to each tumor volume was derived from the individual dose plans. Mean total dose was 59.9 Gy (range: 30-80 Gy). All but 3 patients were followed until death. For local control analysis, each tumor was analyzed separately, and its remission status was determined in serial follow-up CT scans. A total of 784 CT scans were analyzed. Actuarial local control analysis was performed for the 192 separated tumor volumes, and survival analysis was performed for the 135 patients. Tumor control probability was calculated using a Poisson statistical model. RESULTS Overall 1- and 2-year local control rate was 50% and 37%, respectively. The 2-year local control rate for tumors <50 ccm, 50-200 ccm, and >200 ccm was 51%, 22%, and 10%, respectively (p = 0.02). The 2-year local control rate for dose levels < or = 60 Gy and >60 Gy was 28% and 43% (p < 0.001). For the subgroup of 147 tumors smaller than 100 ccm, the local control rate increased up to 70% (1 year) and 51% (2 years) with doses of more than 60 Gy. For tumors larger than 100 ccm, no dose effect was seen. Only 2 of 45 tumors >100 ccm were controlled more than 2 years. Multivariate analysis revealed tumor volume, total dose, histopathologic type, and grading as significant and independent prognostic factors for local control. The number of delay days by split course (if used) and application of chemotherapy was not found to influence local control. Overall 1- and 2-year survival rate was 42% and 13%. Total radiation dose, chemotherapy, and T and N stage---but not tumor volume---were found to be independent and significant prognostic factors for survival in multivariate analysis. CONCLUSION Tumor volume is an important predictor of local control in NSCLC. We found a clear dose effect for local control and survival in NSCLC. Long-term local control for a significant proportion of patients seems possible for small tumors only (<100 ccm, i.e., maximum diameter 6 cm) with doses of 70 Gy and more. Tumors of > or = 100 ccm are unlikely to be controlled long term by conventional doses up to 70 Gy. These results support dose escalation in patients with NSCLC.

Dose–Response Relationship for Image-Guided Stereotactic Body Radiotherapy of Pulmonary Tumors: Relevance of 4D Dose Calculation

PURPOSE To evaluate outcome after image-guided stereotactic body radiotherapy (SBRT) for early-stage non-small-cell lung cancer (NSCLC) and pulmonary metastases. METHODS AND MATERIALS A total of 124 patients with 159 pulmonary lesions (metastases n = 118; NSCLC, n = 41; Stage IA, n = 13; Stage IB, n = 19; T3N0, n = 9) were treated with SBRT. Patients were treated with hypofractionated schemata (one to eight fractions of 6-26 Gy); biologic effective doses (BED) to the clinical target volume (CTV) were calculated based on four-dimensional (4D) dose calculation. The position of the pulmonary target was verified using volume imaging before all treatments. RESULTS With mean/median follow-up of 18/14 months, actuarial local control was 83% at 36 months with no difference between NSCLC and metastases. The dose to the CTV based on 4D dose calculation was closely correlated with local control: local control rates were 89% and 62% at 36 months for >100 Gy and <100 Gy BED (p = 0.0001), respectively. Actuarial freedom from regional and systemic progression was 34% at 36 months for primary NSCLC group; crude rate of regional failure was 15%. Three-year overall survival was 37% for primary NSCLC and 16% for metastases; no dose-response relationship for survival was observed. Exacerbation of comorbidities was the most frequent cause of death for primary NSCLC. CONCLUSIONS Doses of >100 Gy BED to the CTV based on 4D dose calculation resulted in excellent local control rates. This cutoff dose is not specific to the treatment technique and protocol of our study and may serve as a general recommendation.