Gerd Schmitt

Chemoradiation With and Without Surgery in Patients With Locally Advanced Squamous Cell Carcinoma of the Esophagus

PURPOSE Combined chemoradiotherapy with and without surgery are widely accepted alternatives for the curative treatment of patients with locally advanced esophageal cancer. The value of adding surgery to chemotherapy and radiotherapy is unknown. PATIENTS AND METHODS Patients with locally advanced squamous cell carcinoma (SCC) of the esophagus were randomly allocated to either induction chemotherapy followed by chemoradiotherapy (40 Gy) followed by surgery (arm A), or the same induction chemotherapy followed by chemoradiotherapy (at least 65 Gy) without surgery (arm B). Primary outcome was overall survival time. RESULTS The median observation time was 6 years. The analysis of 172 eligible, randomized patients (86 patients per arm) showed overall survival to be equivalent between the two treatment groups (log-rank test for equivalence, P < .05). Local progression-free survival was better in the surgery group (2-year progression-free survival, 64.3%; 95% CI, 52.1% to 76.5%) than in the chemoradiotherapy group (2-year progression-free survival, 40.7%; 95% CI, 28.9% to 52.5%; hazard ratio [HR] for arm B v arm A, 2.1; 95% CI, 1.3 to 3.5; P = .003). Treatment-related mortality was significantly increased in the surgery group than in the chemoradiotherapy group (12.8% v 3.5%, respectively; P = .03). Cox regression analysis revealed clinical tumor response to induction chemotherapy to be the single independent prognostic factor for overall survival (HR, 0.30; 95% CI, 0.19 to 0.47; P < .0001). CONCLUSION Adding surgery to chemoradiotherapy improves local tumor control but does not increase survival of patients with locally advanced esophageal SCC. Tumor response to induction chemotherapy identifies a favorable prognostic group within these high-risk patients, regardless of the treatment group.

HYPERBARIC OXYGEN THERAPY FOR LATE SEQUELAE IN WOMEN RECEIVING RADIATION AFTER BREAST-CONSERVING SURGERY

PURPOSE Persisting symptomatology after breast-conserving surgery and radiation is frequently reported. In most cases, symptoms in the breast resolve without further treatment. In some instances, however, pain, erythema, and edema can persist for years and can impact the patients quality of life. Hyperbaric oxygen therapy was shown to be effective as treatment for late radiation sequelae. The objective of this study was to assess the efficacy of hyperbaric oxygen therapy in symptomatic patients after breast cancer treatment. PATIENTS AND METHODS Forty-four patients with persisting symptomatology after breast-conservation therapy were prospectively observed. Thirty-two women received hyperbaric oxygen therapy in a multiplace chamber for a median of 25 sessions (range, 7-60). One hundred percent oxygen was delivered at 240 kPa for 90-min sessions, 5 times per week. Twelve control patients received no further treatment. Changes throughout the irradiated breast tissue were scored prior to and after hyperbaric oxygen therapy using modified LENT-SOMA criteria. RESULTS Hyperbaric oxygen therapy patients showed a significant reduction of pain, edema, and erythema scores as compared to untreated controls (p < 0.001). Fibrosis and telangiectasia, however, were not significantly affected by hyperbaric oxygen therapy. Seven of 32 women were free of symptoms after hyperbaric oxygen therapy, whereas all 12 patients in the control group had persisting complaints. CONCLUSIONS Hyperbaric oxygen therapy should be considered as a treatment option for patients with persisting symptomatology following breast-conserving therapy.

Remission Rates in Breast Cancer Treated with Preoperative Chemotherapy and Radiotherapy

Purpose: Evaluation of remission rates after neoadjuvant chemotherapy alone or followed by preoperative radiotherapy. Patients and Methods: 194 women with 198 biopsy-proven breast tumors were evaluated in this retrospective study. Of the 198 cases evaluated, 64 received neoadjuvant chemotherapy followed by surgery and adjuvant irradiation (CT group). In 134 cases, sequential preoperative chemo-/radiotherapy (CT-RT group) was given. In both groups, endocrine treatment was initiated in case of positive hormone receptor status after chemotherapy. The whole breast was homogeneously irradiated using 2-Gy fractions up to a total dose of 50 Gy, followed by a boost of 6–11 Gy to the tumor. Results: A histologically proven complete remission (pCR) was achieved in 3% (2/64) in the CT and in 42% (56/134) in the CTRT group. The logistic regression analysis, including clinical tumor category (cT), lymph node (cN) and metastasis status (cM), grading (G), hormone receptor status (HRS), number of preoperative chemotherapy cycles, preoperative tumor volume, and preoperative radiotherapy, revealed that HRS (p = 0.0232) and radiotherapy (p < 0.0001) were significant factors for achieving pCR. Conclusion: Combination of neoadjuvant chemo-/radiotherapy results in significantly higher rates of complete remission than neoadjuvant chemotherapy alone. The significance for tumor-free and overall survival has to be evaluated.Zielsetzung: Bestimmung der Remissionsraten von Mammatumoren nach alleiniger neoadjuvanter Chemotherapie oder präoperativer Chemo- und Strahlentherapie. Patienten und Methodik: In dieser retrospektiven Arbeit wurden 194 Patientinnen mit 198 Mammatumoren untersucht. Von den 198 Fällen erhielten 64 eine neoadjuvante Chemotherapie mit anschließender Operation und adjuvanter Radiotherapie (CT-Gruppe). In 134 Fällen wurde eine sequentielle präoperative Chemo-/Strahlentherapie appliziert (CT-RT-Gruppe). Bei positivem Hormonrezeptorstatus erfolgte in beiden Behandlungsgruppen die endokrine Therapie nach Abschluss der Chemotherapie. Die gesamte Brust wurde homogen mit 2-Gy-Einzeldosen bis zu einer Gesamtdosis von 50 Gy bestrahlt, gefolgt von einem Tumorbettboost von 6–11 Gy. Ergebnisse: Eine histologisch gesicherte komplette Remission (pCR) wurde bei 3% der Patientinnen (2/64) in der CT- und bei 42% (56/134) in der CT-RT-Gruppe erreicht. Die logistische Regressionsanalyse, die klinisches Tumorstadium (cT), Lymphknoten-(cN) und Metastasierungsstatus (cM), Grading (G), Hormonrezeptorstatus (HRS), Anzahl der präoperativen Chemotherapiezyklen, präoperatives Tumorvolumen und präoperative Radiotherapie beinhaltete, zeigte, dass HRS (p = 0,0232) und Radiotherapie (p < 0,0001) signifikante Faktoren für das Erreichen einer pCR waren. Schlussfolgerung: Die Kombination von neoadjuvanter Chemo-/Radiotherapie resultiert in signifikant höheren Raten kompletter Remissionen als die alleinige präoperative Chemotherapie. Die Signifikanz für das tumorfreie und das Gesamtüberleben muss noch evaluiert werden.

The role of neutrons in the treatment of soft tissue sarcomas.

Two‐hundred twenty one patients with soft tissue sarcoma were treated from 1978 to 1983. Treatment was nonrandomized and consisted of neutron irradiation in 94 cases with gross tumor. Treatment was nonrandomized and consisted of neutron boost irradiation after photon‐irradiation or electron‐irradiation in 127 cases with no gross tumor after surgery. Patient distribution according to UICC (1978) criteria was 15, 100, and 106 of T1, T2, and T3 respectively. Distribution by pathologic grade was 54, 107, and 60 for Grade 1, Grade 2, and Grade 3 tumors. Distribution by tumor residuum after surgery was 23 cases without microscopic disease (R0), 104 with miroscopic disease (R1), and 94 with gross residuum (R2) or nonoperative disease. Five‐year follow‐up reveals a significant difference (P = 0.024) in disease‐free survival (DFS) for T1 (60%), T2 (71%), and T3 (29%, P = 0.016) tumors. Similarly, there are significant DFS differences among G 1 (74%), G 2 (48%, P = 0.035), and G 3 lesions (22%, P = 0.024). The impact of tumor bulk or residuum on DFS after operation is significant when comparing R0 (87%) and R1 (65%) disease (P = 0.042). The 5‐year survival of patients who had gross residuum (R2) after surgery was significantly worse (26%, P = 0.003). Ninety percent of patients failed treatment locally and distally within 2 years. The late morbidity rate was 27% for neutron and 7% for neutron‐boost irradiation. In our series and reported photon data, local control rates for tumors 5 to 10 cm with neutrons were 76% and 53%, respectively. Low energy (d(14) + Be) neutrons are considered beneficial in the postoperative treatment of well‐differentiated soft tissue sarcomas where gross tumor remains. Neutron‐boost irradiation is of potential benefit in the treatment after operation of T2‐3, and G 1‐2 tumors if there is microscopic residual tumor.

Treatment of radiation proctitis with hyperbaric oxygen: What is the optimal number of HBO treatments?

AimOur objective was to investigate the effectiveness of hyperbaric oxygenation (HBO) in the treatment of radiation proctitis. The current literature was reviewed with regard to the necessary number of HBO treatments.Patients and MethodsTwo patients with proctitis after pelvic irradiation were treated with 40 and 38 HBO treatments, respectively. Hyperbaric oxygenation was delivered at 240 kPa over 90 min.ResultsIn one patient, proctosigmoidoscopy showed a significant improvement after 40 HBO sessions. The other patient interrupted therapy after 38 HBO treatments without subjective change. The reported number of HBO sessions for a succesful treatment of radiation proctitis ranges from 12 to 90.ConclusionHBO should be considered before more invasive treatment modalities are performed for radiation proctitis.ZusammenfassungZielDie Effektivität hyperbarer Oxygenation (HBO) zur Behandlung der Strahlenproktitis wurde untersucht. Literaturdaten wurden unter der Fragestellung zusammengestellt, wie viele HBO-Therapien für einen Behandlungserfolg notwendig sind.Patienten und MethodelZwei Patienten mit radiogener Proktitis nach Beckenbestrahlung erhielten 40 bzw. 38 HBO-Therapien. Die hyperbare Oxygenation dauerte pro Sitzung 90 Minuten bei 240 kPa.ErgebnisseBei einer Patientin zeigte sich bei der proktoskopischen Verlaufsuntersuchung nach 40 HBO-Therapien eine deutliche Besserung der Strahlenproktitis. Der andere Patient brach die Therapie nach 38 HBO-Behandlungen ohne subjektive Befundbesserung ab. In der Literatur zur Behandlung der Strahlenproktitis mit HBO schwankt die Anzahl der notwendigen Behandlungen von 12 bis 90.SchlußfolgerungHBO sollte als Behandlungsalternative in Erwägung gezogen werden, bevor invasivere Therapieverfahren zur Behandlung einer Strahlenproktitis angewendet werden.

Radiotherapy and high-dose chemotherapy in advanced Ewing's tumors.

Background: Ewings tumors are sensitive to radio- and chemotherapy. Patients with multifocal disease suffer a poor prognosis. Patients presenting primary bone marrow involvement or bone metastases at diagnosis herald a 3-year disease-free survival below 15%. The European Intergroup Cooperative Ewings Sarcoma Study (EICESS) has established the following indications for high-dose therapy in advanced Ewings tumors: Patients with primary multifocal bone disease, patients with early (<2 years after diagnosis) or multifocal relapse. Patients and Method: As of 1987, 83 patients have been treated in the EICESS group, 39 of them at the transplant center in Düsseldorf, who have been analyzed here. All individuals received 4 courses of induction chemotherapy with EVAJA and stem cello collection after course 3 and 4. Consolidation radiotherapy of the involved bone compartments was administered in a hyperfractionated regimen 2 times 1.6 Gy per day, up to 22.4 Gy simultaneously to course 5 and 22.4 Gy to course 6 of chemotherapy. The myeloablative chemotherapy consisted of melphalan and etaposide (ME) in combination with 12 Gy TBI (Hyper-ME) or Double-ME with whole lung irradiation up to 18 Gy (without TBI). Results: The survival probability at 40 months was 31% (44% DOD; 15% DOC). Pelvic infiltration did not reach prognostic relevance in this cohort. Radiotherapy encompassed 75% of the bone marrow at maximum (average 20%). Engraftment was not affected by radiotherapy. Conclusion: High-dose chemotherapy can improve outcome in poor prognostic advanced Ewings tumors. The disease itself remains the main problem. The expected engraftment problems after intensive radiotherapy in large volumes of bone marrow can be overcome by stem cell reinfusion.Hintergrund: Ewing-Tumoren sind radio- und chemosensibel. Im metastasierten Stadium ist die Prognose schlecht. Patienten mit Knochen- oder Knochenmarkinfiltration haben nach drei Jahren eine erkrankungsfreie Überlebenswahrscheinlichkeit von weniger als 15%. Die EICESS-Gruppe hat folgende Indikationen für die Hochdosistherapie bei fortgeschrittenen Ewing-Tumoren etabliert: Patienten mit primären multifokalen Knochenmetastasen und Patienten mit einem frühen (<2 Jahren) oder multifokalen Rezidiv. Patienten und Methode: Seit 1987 wurden 83 Patienten in der EICESS-Gruppe behandelt, 39 von ihnen in Düsseldorf, deren Analyse hier vorgestellt werden soll. Alle Patienten erhielten vier Kurse einer Induktionschemotherapie mit EVAJA und nachfolgender Stammzellasservation. Anschließend erfolgte eine konsolidierende Bestrahlung aller befallenen Knochenkompartimente, hyperfraktioniert, 2mal 1,6 Gy pro Tag bis zu einer Zielvolumendosis von 22,4 Gy simultan zu Kurs 5 und 6 der Chemotherapie, entsprechend 44,8 Gy Gesamtdosis. Die myeloablative Therapie bestand aus Melphalan und Etoposid (ME) und 12 Gy TBI (Hyper-ME) oder bei zusätzlichem Lungenbefall aus zwei Kursen ME und Ganzlungenbestrahlung bis 18 Gy (Double-ME). Ergebnisse: Die Überlebenswahrscheinlichkeit nach 40 Monaten betrug 31% (44% starben am Tumor und 15% an Komplikationen). Beckentumoren hatten in dieser Gruppe keine prognostische Relevanz. Im Durchschnitt wurden 20% des Knochenmarkvolumens (maximal 75%) bestrahlt. Das Engraftment wurde durch die Bestrahlung nicht beeinflußt. Schlußfolgerung: Die Prognose bei multifokalen, fortgeschrittenen Ewing-Tumoren kann durch die Hochdosistherapie verbessert werden. Das Hauptproblem bleibt die Krankheit selbst. Die nach intensiver Strahlentherapie großer Knochenmarkvolumia erwarteten Engraftment-Probleme können durch Stammzellreinfusion überwunden werden.

Simultaneous Radiotherapy and Chemotherapy with Carboplatin in Inoperable Squamous Cell Carcinoma of the Head and Neck: A Phase II Study

Fifty-six untreated patients with inoperable squamous cell carcinoma of the head and neck were treated with carboplatin 70 mg/m2 i.v. daily on days 1-5 and 29-33 in combination with simultaneous conventional radiation up to a target volume dose of 50 Gy. Depending on tumor response and upon recommendation of surgeons, 21 of 56 patients underwent surgery after a radiation dose of 50 Gy and two courses of carboplatin. Patients who showed pCR after surgery received no further radiotherapy. In all other patients radiotherapy was continued using a shrinking field technique up to a target absorbed dose of 70-74 Gy. Combined modality induced 66% complete remission (CR) and an overall response rate of 98%. After completion of the whole treatment program (combined modality +/- surgery) 53 (94%) of the 56 patients were disease free. The median survival for all patients is 25+ months and the percentage of two-year survivors is 53%. Myelosuppression was the most frequent toxicity, but rarely was severe; leukopenia and thrombocytopenia of WHO grade 3 occurred in 21% of the patients. No other toxicities above WHO grade 2 occurred. Nephrotoxicity, neurotoxicity and ototoxicity were not seen. The addition of carboplatin did not increase the rate of surgical complication over that expected for preoperative radiotherapy. Two patients died of pulmonary embolism after surgery. Combined modality with carboplatin and simultaneous radiation is a highly active and well-tolerated regimen for untreated patients with inoperable squamous cell carcinoma of the head and neck.

Status report of the NAC particle therapy programme.

SummaryThe 200 MeV cyclotron facility at the National Accelerator Centre has been operational since 1987. Between September 1988 and December 1997 a total of 973 patients (26,916 fields) had been treated on the 66 MeV p+Be isocentric neutron therapy system. Patients are currently being treated according to several protocols, including tumors of the head and neck, salivary gland and breast and soft tissue sarcomas, uterine sarcomas and paranasal sinuses. A multiblade post-collimator trimmer has recently being installed. This device procides improved neutron beam shaping capability. Between September 1993 and December 1997 a total of 243 patients (4008 fields) had been treated (mainly intracranial stereotactic irradiations) on the fixed horizontal 200 MeV proton therapy facility. The facility incorporates an innovative automatic patient positioning system. Two new fixed beam lines for proton therapy are presently being designed (horizontal and 30° to the vertical) for an existing unused treatment vault. Spot scanning systems will be developed for both beam lines.

Effect of recombinant human granulocyte colony stimulating factor (r-metHuG-CSF) as an adjunct to large-field radiotherapy: A phase I study

PURPOSE To test the feasibility of recombinant human granulocyte colony stimulating factor application during large-field radiotherapy. METHODS AND MATERIALS Fifteen patients with clinically and histologically proven malignancy who received large-field radiotherapy entered this study. Administration of recombinant granulocyte colony stimulating factor (G-CSF) at a dose of 300 microgram subcutaneously was started on Friday and was continued on Saturday and Sunday after the first radiotherapy treatment, which began on the Monday before. In this way four courses of G-CSF were applied every Friday, Saturday, and Sunday during the radiotherapy period. Absolute neutrophil cell (ANC) and blood counts were monitored twice a week and compared to a second group of 15 patients who received large-field radiotherapy without G-CSF. Before and at the end of every cycle of G-CSF, ANC, blood counts, and biochemistry were measured. We compared the myelotoxicity of the patients treated with G-CSF with 15 patients without G-CSF treated at the same period with large-field radiotherapy, in match pair technique. RESULTS G-CSF increased the ANC throughout the period of irradiation, and the treatment time needed for competing radiotherapy was shorter in the group who received G-CSF. Fourteen of 15 patients who received G-CSF treatment completed large-field radiotherapy without pause. Only 1 of 15 patients not receiving G-CSF was able to receive radiation treatment on schedule. Patients receiving G-CSF completed treatment with the mantle-field technique in 24 days and those with the abdominal bath technique in 26.5 days. Conversely, patients treated without G-CSF completed treatment with the mantle-field technique in 30.5 days and those with the abdominal bath technique in 36 days. The most frequent side effect was musculoskeletal pain. CONCLUSION The prophylactic application of G-CSF during large-field radiotherapy before the onset of neutropenia was feasible in this schedule. Whether or not this shortening of treatment duration will translate into an improvement in efficacy is not clear.

The neutron therapy clinical programme at the National Accelerator Centre (NAC)

A total of 721 patients were treated in the neutron therapy programme at NAC from February 1989-March 1995 with a p(66)/Be isocentric unit. The preliminary results showed: 3-year local control and survival probabilities of 57 and 79% respectively for advanced salivary gland tumours; increased local control for twice-daily neutron therapy for advanced head and neck cancer compared with photon therapy; local control rates of 68 and 83% for locally advanced breast cancer treated with 17 and 19 Gy respectively; complete response rates of 67% for macroscopic residual soft tissue sarcomas and those with irresectable disease of less than 10 cm; complete response rate of 56% for macroscopic residual uterine sarcoma with a median follow up of 38 months; 2-year local control rate and survival of 44 and 38% respectively for advanced squamous carcinoma of the maxillary antrum; complete response rate of 38% for advanced osteosarcomas and chondrosarcomas.