Stereotactic body radiotherapy (SBRT) for multiple pulmonary oligometastases: Analysis of number and timing of repeat SBRT as impact factors on treatment safety and efficacy.

BACKGROUND: Stereotactic body radiotherapy (SBRT) for oligometastatic disease is characterized by an excellent safety profile; however, experiences are mostly based on treatment of one single metastasis. It was the aim of this study to evaluate safety and efficacy of SBRT for multiple pulmonary metastases. PATIENTS AND METHODS: This study is based on a retrospective database of the DEGRO stereotactic working group, consisting of 637 patients with 858 treatments. Cox regression and logistic regression were used to analyze the association between the number of SBRT treatments or the number and the timing of repeat SBRT courses with overall survival (OS) and the risk of early death. RESULTS: Out of 637 patients, 145 patients were treated for multiple pulmonary metastases; 88 patients received all SBRT treatments within one month whereas 57 patients were treated with repeat SBRT separated by at least one month. Median OS for the total patient population was 23.5 months and OS was not significantly influenced by the overall number of SBRT treatments or the number and timing of repeat SBRT courses. The risk of early death within 3 and 6 months was not increased in patients treated with multiple SBRT treatments, and no grade 4 or grade 5 toxicity was observed in these patients. CONCLUSIONS: In appropriately selected patients, synchronous SBRT for multiple pulmonary oligometastases and repeat SBRT may have a comparable safety and efficacy profile compared to SBRT for one single oligometastasis.

Nomogram based overall survival prediction in stereotactic body radiotherapy for oligo-metastatic lung disease.

BACKGROUND: Radical local treatment of pulmonary metastases is practiced with increasing frequency due to acknowledgment and better understanding of oligo-metastatic disease. This study aimed to develop a nomogram predicting overall survival (OS) after stereotactic body radiotherapy (SBRT) for pulmonary metastases. PATIENTS AND METHODS: A multi-institutional database of 670 patients treated with SBRT for pulmonary metastases was used as training cohort. Cox regression analysis with bidirectional variable elimination was performed to identify factors to be included into the nomogram model to predict 2-year OS. The calibration rate of the nomogram was assessed by plotting the actual Kaplan-Meier 2-year OS against the nomogram predicted survival. The nomogram was externally validated using two separate monocentric databases of 145 and 92 patients treated with SBRT for pulmonary metastases. RESULTS: The median follow up of the trainings cohort was 14.3months, the 2-year and 5-year OS was 52.6% and 23.7%, respectively. Karnofsky performance index, type of the primary tumor, control of the primary tumor, maximum diameter of the largest treated metastasis and number of metastases (1 versus >1) were significant prognostic factors in the Cox model (all p<0.05). The calculated concordance-index for the nomogram was 0.73 (concordance indexes of all prognostic factors between 0.54 and 0.6). Based on the nomogram the training cohort was divided into 4 groups and 2-year OS ranged between 24.2% and 76.1% (predicted OS between 30.2% and 78.4%). The nomogram discriminated between risk groups in the two validation cohorts (concordance index 0.68 and 0.67). CONCLUSIONS: A nomogram for prediction of OS after SBRT for pulmonary metastases was generated and externally validated. This tool might be helpful for interdisciplinary discussion and evaluation of local and systemic treatment options in the oligo-metastatic setting. KEY MESSAGE: A nomogram for prediction of overall survival after stereotactic body radiotherapy (SBRT) for pulmonary metastases was developed and externally validated. This tool might be helpful for interdisciplinary discussion and evaluation of local and systemic treatment options in the oligo-metastatic setting.

[Errors and hazards in oncology: radiation oncology]. / Fehler und Gefahren: Medikamentöse und strahlentherapeutische Behandlung von -Kopf-Hals-Malignomen.

Adverse effects and hazards which have their origin from radiation using conventional techniques like 3-D conformal radiotherapy and total radiation doses are well known. However little is known about the sprectum of especially late toxicity after radiation using new technologies like intensity modulated radiotherapy (IMRT) combined with novel target volume and dose concepts. Since IMRT allows for selective protection of the large salivary glands this technique improves the intermediate term quality of life and is the standard of care despite many details need further prospective evaluation. Combining cytotoxic drugs and radiotherapy yield improved survival in well-defined high risk patients. However morbidity and mortality of these protocols are high and deserve special expertise and supportive therapy. EGF-receptor antibodies have gained well defined indications, albeit specific toxicities in combination with irradiation deserve prospective studies and special attention.

Prognostic factors in squamous cell carcinoma of the head and neck.

Therapy for squamous cell carcinoma of head and neck relies on surgery, radiotherapy and chemotherapy, mostly a combination thereof. In patients treated with curative intent, the intensity of therapy is adapted to the supposed prognosis and should be defined upon prognostic factors. Besides classical prognostic parameters, T, N and M stage, the presence of extranodal growth (extracapsular spread, ECS), tumor volume, lymph node burden, extent of tumor necrosis, histologic grading, but also type of treatment were determined in consideration of prognosis. The p53 status does not correlate with prognosis in most investigations. The tumor hypoxia seems to be of prognostic value, and strategies to overcome the adverse effect are currently investigated. Not all factors are relevant for all types of treatment. Besides ECS, these new factors so far have rarely been used to stratify prospective combined modality treatment according to the risk of locoregional and distant failure.

Thoracic radiotherapy in the treatment of limited disease of small-cell cancer: sequence and fractionation.

Since two meta-analyses showed improved survival rates at 3 years of approximately 5%, thoracic radiotherapy is accepted as an essential component of optimal management of limited-disease. However, optimal sequencing, timing, fractionation, dose, and field size still remain a matter of controversy. The issue has changed since the traditional doxorubicin-based chemotherapy has been substituted by cisplatin based regimens which clearly produce less acute toxicity and allow concomitant chemoradiation protocols. Up-front radiotherapy seems to improve 5-years survival rates compared to the traditional sequential modality. Different fractionation schedules and escalated total doses are tested prospectively in order to reduce the intrathoracic relapse rate. Increased intensity of intrathoracic radiotherapy seems to augment long term survival rates.

Clinical Implications of 3D-Conformal Radiotherapy.

INTRODUCTION: Local tumor control in cancer patients is the major goal of radiation therapy. More than 10% of cancer patients die as a result of local failure with no evidence of metastatic disease. A local failure can represent the cause of metastastic progression. As most malignant tumors show a steep dose-response curve, an increased total dose may result in improved long-term cure rates at least in a subset of patients. But dose escalation is often not possible with conventional radiotherapy techniques because raising the dose to the target also raises the dose to surrounding normal tissue. Recent technical developments gave way to the introduction of 3-dimensional conformal radiation therapy (3DCRT) techniques into clinical practice. Copyright 2000 S. Karger GmbH, Freiburg

Daily amifostine given concomitantly to chemoradiation in head and neck cancer. A pilot study.

BACKGROUND: In patients with loco-regionally advanced head and neck cancer conventionally fractionated radiotherapy alone results in poor loco-regional control and survival rates. Treatment intensification by simultaneous administration of cytotoxic drugs produces higher acute morbidity. Therefore chemical radioprotection of normal tissues may be of clinical benefit. PATIENTS AND METHODS: In a pilot study patients with advanced nonresectable head and neck cancer treated with conventionally fractionated radical radiotherapy (60 to 66 Gy total doses) and concomitantly given 5-fluorouracil as protracted venous infusion, 250 mg/sqm/24 h over the entire treatment period were given amifostine 300 mg absolutely before each fraction. Acute treatment related morbidity was scored according to CTC classification and loco-regional control and survival rates were estimated. Comparison was made with a historical control group of identical chemoradiation but without amifostine application. RESULTS: Chemoradiation induced oral mucositis was delayed and showed significant lower degrees at all 10 Gy increments (p < 0.05) except 60 Gy and over (p > 0.05). No significant toxicity was recorded with respect to blood pressure, serum calcium, potassium, hematologic parameters, emesis, nausea or body weight loss. Progression free survival and overall survival probability at 2 years were not statistically different in both cohorts. CONCLUSION: Amifostine given before each fraction of radiotherapy over 6 weeks has no cumulative toxicity, was well tolerated and may reduce treatment induced oral mucositis. No tumor protective effect was observed.

Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study.

PURPOSE: A prospective randomized multicenter trial was performed to evaluate the contribution of simultaneously administered chemotherapy (CT) and radiotherapy (RT) in previously untreated patients with unresectable stage III/IV head and neck cancer. PATIENTS AND METHODS: Patients with locoregionally advanced head and neck cancer were treated either with RT alone (arm A) or simultaneous RT plus CT (RCT; arm B). RT was identical in both arms and administered in three courses with 13 fractions of 1.8 Gy each twice daily. During one course, from day 3 to 11, 23.4 Gy was delivered. In arm B, cisplatin (CDDP) 60 mg/m2, fluorouracil (5-FU) 350 mg/m2 by intravenous (i.v.) bolus, and leucovorin (LV) 50 mg/m2 by i.v. bolus were given on day 2, and 5-FU 350 mg/m2/24 hour by continuous infusion and LV 100 mg/m2/24 hours by continuous infusion were given from day 2 to 5. Treatment was repeated on days 22 and 44; a total RT dose of 70.2 Gy was administered. Treatment breaks were scheduled from days 12 to 21 and days 34 to 43. RESULTS: From 1989 to 1993, 298 patients were enrolled and 270 patients were assessable. Acute mucositis grade 3 or 4 was more frequent in arm B (38%) than in arm A (16%) (P < .001). Total treatment time was significantly longer in arm B than in arm A (P < .001) due to prolonged breaks. According to hematologic toxicity, scheduled drug doses were given in 74% of patients for the second course and 46% for the third course. The 3-year overall survival rate was 24% in arm A and 48% in arm B (P < .0003). The 3-year locoregional control rate was 17% in arm A and 36% in arm B (P < .004). Both arms showed similar distant failure patterns (arm A, 13 of 140; arm B, 12 of 130). Serious late side effects were not significantly different between treatment arms (arm A, 6.4%; arm B, 10%; not significant). CONCLUSION: Concomitant CT offered improved disease control and survival in advanced head and neck cancer patients. Due to increased acute toxicity, more supportive care is demanded when CT is given simultaneously. Increased total treatment time does not exert a negative impact on outcome in this combined modality regimen.

[The inhalation versus systemic prevention of pneumonitis during thoracic irradiation]. / Inhalative versus systemische Pneumonitisprophylaxe bei Thoraxbestrahlungen.

BACKGROUND: Pneumonitis is a typical subacute reaction of healthy bronchial tissue to thoracic irradiation. The purpose of the present trial was to show whether prophylactic application of steroids in the course of and following radiotherapy would reduce the incidence of pneumonitis. PATIENTS AND METHODS: Fifty-seven patients receiving thoracic irradiation for bronchial carcinoma were assigned to 2 therapeutic groups; half of the patients were given 10 mg of oral prednisolone per day, while the other half received daily inhalative beclomethasone. All patients were evaluated for radiographic signs of pneumonitis. Thirty-two patients received additional investigations for pulmonary diffusion capacity of carbon monoxide. RESULTS: The overall incidence of pneumonitis was 17.6% (10/57 patients). Neither total radiation dose nor mode of fractionation did significantly contribute to the incidence of pneumonitis. Those patients showing a pulmonary diffusion capacity for carbon monoxide of less than 60% prior to radiotherapy had a significantly higher risk of developing pneumonitis (4/7) than patients with a higher diffusion capacity (3/25, p = 0.026). In follow-up period we did not see significant changes in diffusion capacity neither with patients who developed pneumonitis nor with those patients showing no evidence of pulmonary injury. Comparing the chest X-ray there were less radiographic changes consistent with pneumonitis in the inhalative beclomethasone (2/28) than in the oral prednisolone group (8/29, p = 0.045). DISCUSSION: In order to reduce the incidence of pneumonitis in patients receiving thoracic irradiation we support a continuous application of steroids in the course of and following radiotherapy. The inhalative use of beclomethasone has proved to be superior to oral prednisolone due to better local efficacy and decreased unwanted side effects.

[The radiochemotherapy of advanced head-neck tumors--what is certain?]. / Radiochemotherapie bei fortgeschrittenen Kopf-Hals-Tumoren--was ist gesichert?

BACKGROUND: Loco-regional control and survival after radical conventionally fractionated radiotherapy remains poor in advanced squamous cell head and neck cancer. Therefore during the last 2 decades new modalities were investigated including unconventional fractionation and radiochemotherapy. PATIENTS AND METHODS: The literature is reviewed and results of a novel protocol of the German Cancer Society ARO 89-1 applying chemotherapy and radiotherapy synchronously are analysed in order to define the current role of chemotherapy in the treatment of newly diagnosed loco-regionally advanced head and neck cancer. RESULTS: Despite high response rates achieved by induction chemotherapy ultimate survival has not changed in the vast majority of studies reported. Provided the loco-regional disease is controlled 3 courses of active combination chemotherapy reduce the incidence of distant metastases from 25% to 15%. In a prospective randomized multicenter study with 270 evaluable patients conducted from 1989 to 1993 3 courses of split course accelerated radiotherapy were compared with 3 courses radio-chemotherapy. After combined modality loco-regional control increased from 17% to 34% (p < 0.014) and overall survival from 24% to 48% (p < 0.0003). Also fast alternating protocols yield improved loco-regional control rates but not improved survival. When 5-FU is given simultaneously to irradiation continuous infusion rendered superior to bolus injection. Except bleomycin cytotoxic drugs do not increase incidence or severity of chronic radiation sequelae. The total treatment duration considered crucial in radiotherapy alone seems less important in combined modality protocols. CONCLUSION: Sequential radio-chemotherapy protocols should be omitted in favour of simultaneous or fast alternating protocols. Since the latter are more toxic compared to sequential radio-chemotherapy or radiotherapy alone supportive care is mandatory. Future trials should determine new prognostic factors in order to individualize therapy.

[Current status of therapy of CNS metastases of germ cell tumors]. / Derzeitiger Stand der Therapie von ZNS-Metastasen bei Keimzelltumoren.

The incidence of CNS metastases in germ cell tumors is 2-5% and in very advanced disease over 20%. We report on 37 patients in whom CNS metastases were diagnosed with the CAT scanner. Twenty-nine patients were subsequently treated. In 19 cases, treatment consisted of radiotherapy, 1 patient was only operated on, and in 9 cases patients received combined surgery and radiotherapy. Two patients had seminomatous germ cell tumors, 27 patients non-seminomatous tumors. HCG levels were high in 11 cases. In 31 patients the disease was in the advanced stages; in 6 the disease was at the early stage. If there was just a solitary tumor, operation was the preferred mode of treatment. Radiotherapy consisted of 50 GY whole-brain irradiation, with a tumor saturation up to 60 GY. In 2 cases we suspected radiogenic necrosis. There were no other severe side effects. Of the 37 patients, 4 obtained a long-term cure (observation time 34-90 months). Therapy must take all methods of treatment into consideration and should only be carried out in fully equipped medical centers. Only then can we hope to obtain long-term cures in individuals with this usually fatal disease.

[Results of photon therapy of malignant tumors of the parotid gland]. / Ergebnisse der Photonentherapie von malignen Tumoren der Ohrspeicheldrüse.

Between 1971 and 1982 86 patients have been treated because of a malignant tumor of the parotid gland. 64 patients have been irradiated after complete (n = 49) or incomplete (n = 15) first resection. 12/64 (19%) relapsed locally. The loco-regional tumor control rate five and ten years after postoperative radiotherapy is 72%, 85% after complete resection, and 22% after incomplete resection (p less than 0.01). Tumor size and nodal disease are of prognostic value. Disease-free survival in patients without lymph nodes is 53%, with lymph node metastases 31% after five years (p less than 0.05). Small tumors (T1, 2) have a better local control rate compared to locally advanced tumors (five years: 83% vs. 53%, p less than 0.05). No difference was found neither for the total dose nor the histology of the tumor. Distant metastases became apparent after median eleven months.

[The results of simultaneous radio-chemotherapy in advanced head and neck tumors]. / Ergebnisse der simultanen Radio-Chemotherapie bei fortgeschrittenen Kopf-Hals-Tumoren.

Patients suffering from locally advanced squamous cell carcinoma of the head and neck were treated with three courses of simultaneous radio-chemotherapy. Chemotherapy consisted of cis-platinum, 60 mg/m2 i.v. on day 2; 5-FU, 350 mg/m2 i.v. bolus on day 2; leucovorin calcium, 50 mg/m2 i.v. on day 2; 5-FU, 350 mg/m2/24 hrs continuously infused over 96 hrs from day 2 to day 5 and leucovorin calcium, 100 mg/m2/24 hrs continuously infused over 96 hours from day 2 to day 5 each course. Radiotherapy was administered from day 3 to day 11. 23.4 Gy were given in 13 fractions, twice a day with a minimum interval of four hours. This schedule was repeated on days 22 and 44. The total radiation dose amounted to 70.2 Gy/51 days. From 1984 to 1986, 62 patients were entered in this prospective trial. Three patients deceased due to massive hemorrhage during therapy, one patient was not eligible due to a second malignancy. 5/58 evaluable patients had a UICC-Stage III cancer, 53/58 had a UICC-Stage IV cancer. 48/58 (81%) showed a clinically complete response to therapy, 10/58 (17%) achieved partial response three months after the end of treatment. In 16/58 patients loco-regional cancer was not controlled (minimum follow-up 2 years), in 12/58 distant metastases occurred. Loco-regional control rate is estimated at 66% +/- 7% (Kaplan Maier).

Cisplatin, fluorouracil with leucovorin calcium enhancement, and synchronous accelerated radiotherapy in the management of locally advanced head and neck cancer: a phase II study.

In a phase II study, patients with locally advanced squamous cell carcinoma of the head and neck were treated with simultaneous chemoradiotherapy. Treatment was divided into three courses. Chemotherapy consisted of cis-diamminedichloroplatinum (II) (cisplatin [cis-DDP]) 60 mg/m2 intravenously (IV), fluorouracil (5-FUra) 350 mg/m2 IV, and folinic acid (leucovorin calcium [FA]) 50 mg/m2 IV on day 2 as bolus, and 5-FUra 350 mg/m2 over 24 hours and FA 100 mg/m2 over 24 hours on days 2 through 5. Radiotherapy consisted of 23.4 Gy over nine days divided into 13 fractions of 1.8 Gy each delivered twice a day from day 3 through day 11. This regimen was repeated on days 22 and 44. Total radiation dose amounted to 70.2 Gy over 51 days. Between August 1984 and October 1986, 62 (modified AJCC stage III, four; IV A, eight; IV B, 50) consecutive patients were entered in the study. Three patients died during treatment due to tumor hemorrhage. Of 59 patients, 48 (81%) achieved a clinically complete response (cCR); 11 (19%) achieved a partial response (cPR). Mean follow-up of the surviving patients was 29+ (24 to 44) months. Actuarial 2-year survival probability is 52%, including three early deaths from tumor bleeding. Tumor and neck nodes control rates at 2 years were 92% for stage III and IV A patients and 65% for stage IV B patients. Patients with cCR had a significantly better 2-year tumor and neck nodes control probability compared with patients who achieved cPR after therapy (P less than .001). Six patients developed distant metastases. Overall toxicity was tolerable, mucositis particularly was not a limiting factor.

Simultaneous chemo-radiotherapy with 5-FU/folinic acid/cis-platinum and accelerated split-course radiation in advanced head and neck cancer.

In a clinical phase-II trial, 62 previously untreated patients suffering from unresectable stage III (4 patients) and IV (56 patients) squamous cell carcinoma of the head and neck were treated with a simultaneous chemoradiotherapy consisting of a 5-fluorouracil/folinic acid/cis-platinum combination and of an accelerated split-course radiotherapy. As results, 3 patients died from tumor arrosion bleeding during the treatment. The median follow-up time of the surviving patients is 27+ months (range 18-44 months). Forty-eight out of 62 patients (77%) achieved complete remission, and 11/62 patients (18%) partial remission. Presently, 32 patients (52%) are without evidence of disease. The actuarial 3-year overall survival rate (Kaplan-Meier method) out of 62 patients is 53%. The actuarial disease-free survival and local tumor control rates at 3 years are 58% and 72%. Toxicity on oral mucosa was severe but tolerable, bone marrow depression was marked but not life-threatening. In conclusion, this combined simultaneous modality approach is highly effective in locally advanced head and neck cancer. It appears to provide superior survival and local control rates as compared to conventional radiotherapy or sequential chemo-radiotherapy.