Mitomycin C with continuous fluorouracil or with cisplatin in combination with radiotherapy for locally advanced anal cancer (European Organisation for Research and Treatment of Cancer phase II study 22011-40014).

PURPOSE: To assess the feasibility and activity of radio-chemotherapy with mitomycin C (MMC) and cisplatin (CDDP) in locally advanced squamous cell anal carcinoma with reference to radiotherapy (RT) combined with MMC and fluorouracil (5-FU). PATIENTS AND METHODS: Patients with measurable disease >4 cmN0 or N+ received RT (36Gy+2 week gap+23.4Gy) with either MMC/CDDP or MMC/5-FU (MMC 10mg/m(2) d1 of each sequence; 5-FU 200mg/m(2)/day c.i.v. daily; CDDP 25mg/m(2) weekly). Forty patients/arm were needed to exclude a RECIST objective response rate (ORR), 8 weeks after treatment, of <75% (Fleming 1, alpha=10%, beta=10%). RESULTS: The ORR was 79.5% (31/39) (lower bound confidence interval [CI]: 68.8%) with MMC/5-FU versus 91.9% (34/ 37) (lower bound CI: 82.8%) with MMC/CDDP. In the MMC/5-FU group, two patients (5.1%) discontinued treatment due to toxicity versus 11 (29.7%) in the MMC/CDDP group. Nine grade 3 haematological events occurred with MMC/CDDP versus none with 5-FU/MMC. The rate of other toxicities did not differ. There was no toxic death. Thirty-one patients in the MMC/5-FU arm (79.5%) and 18 in the MMC/CDDP arm (48.6%) were fully compliant with the protocol treatment (p=0.005). CONCLUSIONS: Radio-chemotherapy with MMC/CDDP seems promising as only MMC/CDDP demonstrated enough activity (RECIST ORR >75%) to be tested further in phase III trials; MMC/5-FU did not. MMC/CDDP also had an overall acceptable toxicity profile.

Lymphatic mapping and sentinel lymph node biopsy in epidermoid carcinoma of the anal canal.

AIM: Although 15-25% of patients with anal cancer present with superficial inguinal lymph node metastases but the routine application of groin irradiation is controversial because of serious side effects. Inguinal sentinel lymph node biopsy (SLNB) can be used to select patients appropriately for inguinal radiation. The study evaluates the efficiency and clinical impact of SLNB. METHODS: Forty patients with anal cancer underwent 1 ml Tc(99m)-Nanocolloid injection in four sites around the tumour. Patients with inguinal radio colloid enrichment were selected for sentinel lymph node biopsy (SLNB). Lymph node status was examined by haematoxylin and eosin (H&E) as well as immunohistochemistry-staining. All SLN-positive patients were scheduled for inguinal radiation; SLN-negative patients with T1 and early T2 tumours were not scheduled for inguinal radiation. RESULTS: SLN were detected in 36/40 patients. Three common patterns of lymphatic drainage were observed: mesenterial, iliacal and inguinal. Twenty patients with inguinal SLN underwent SLN-biopsy. 6/20 patients were SLN-positive. In 10/20 patients SLNB altered the therapy plan--four patients with T1-tumours and positive SLN had additional groin irradiation, whereas 6 patients with small T2-tumors and tumour-free inguinal SLN did not undergo inguinal irradiation. CONCLUSIONS: Inguinal sentinel node biopsy in anal cancer is efficient and could assist in the decision for inguinal radiation. The validity and safety of the proposed therapeutic algorithm has to be proven by a larger, prospective study.

Sentinel node biopsy in anal cancer - a promising strategy to individualize therapy.

BACKGROUND: In order to individualize the therapy in patients with anal cancer, we evaluated the applicability of the sentinel lymph node (SLN) concept for the staging of inguinal lymph nodes in these patients. PATIENTS AND METHOD: SLN mapping using the radiocolloid technique was performed in 12 patients with histopathologically proven anal cancer. Mean age of the 4 male and 8 female patients was 62 years (range: 37-83 years). All patients underwent injection of (99m)Tc-colloid (Nanocis) in 4 portions around the tumor followed by scintigraphy after 17 h and selective lymph node biopsy in case of nuclide enrichment. The nuclide-enriched lymph node was intraoperatively identified by a hand-held gamma-camera. Histopathological assessment of the harvested SLNs included serial sections and immunohistochemical staining. RESULTS: Enrichment of radiocolloid in lymph nodes was seen in 10 of the 12 patients (detection rate: 83%). SLN biopsy was performed in 9 patients, one patient refused the SLN biopsy (SLNB). 4 patients revealed tumor-infiltrated sentinel lymph nodes including one patient with bilateral biopsy, who showed metastases unilaterally. The remaining 5 patients had no evidence of metastases in the excised SLNs. CONCLUSION: It is feasible to evaluate the nodal status of the groin in patients with anal cancer using the radiocolloid technique. Preliminary results indicate a refined diagnostic work-up for anal cancer patients, potentially improving the results of clinical and sonographical examinations. Further application of the method may lead to an individualized treatment of patients with anal cancer.

[The role of radiotherapy in the treatment of bone neoplasms]. / Stellung der Strahlentherapie in der Behandlung der Knochentumoren.

Primary malignant bone neoplasms are relatively rare. The most common bone tumors are osteosarcoma,Ewing's sarcoma,chondrosarcoma, fibrosarcoma,malignant fibrous histiocytoma of bone, giant cell tumor, aneurysmal bone cyst and chordoma. These tumors are generally considered to be a radioresistant entities, but it has been suggested that radiotherapy may be effective in a palliative and in some curative situations, if a sufficient dose is given to an adequate volume. Only for the management of primary Ewing's sarcoma the radiation therapy is an essential part in the multimodal therapy concept. The most common bone neoplasms and the role of the radiotherapy are discussed in these chapter.

[Radiotherapy of distant metastases of urological malignant tumors]. / Strahlentherapie von Fernmetastasen urologischer Malignome.

The largest subgroup of patients with metastasised urological malignancies are those with metastases of the bone. Lesions of bones frequently reduce the patients quality of life. Therefore a sufficient therapy is crucial. First of all the appropriate diagnostic procedure of the lesion/lesions is necessary because e the right choice of diagnostic measures may already improve quality of life. Besides the most frequently used local irradiation a systemic radiotherapy may be the adequate therapy in patients with disseminated disease. Renal cell-, bladder and penile cancer respectively are the urological malignancies frequently metastasising into the brain. Adequate diagnostic procedures and therapy are crucial to the patients quality of life for the remaining lifetime. Besides a whole brain irradiation as standard therapy stereotactic radiotherapy is a high precision tool to destroy intracerebral tumour. There are many other locations of metastatic disease (i.e. lymph node or soft tissue metastasis, et cetera) where palliative external beam irradiation may provide relief from symptoms such as pain, lymph oedema or bleeding and thus increase quality of life. Psychological and social care are of great value besides symptom oriented therapy (i.e. radiotherapy, drugs, et cetera) to achieve an optimal palliation/quality of life.

[Remineralization and pain relief in bone metastases after after different radiotherapy fractions (10 times 3 Gy vs. 1 time 8 Gy). A prospective study]. / Remineralisation und Schmerzlinderung von Knochenmetastasen nach unterschiedlich fraktionierter Strahlentherapie (10 mal 3 Gy vs. 1 mal 8 Gy). Eine prospektive Studie.

BACKGROUND: In a prospective randomized trial we examined pain relief and recalcification following radiotherapy for bone metastases. PATIENTS AND METHOD: 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 x 8 Gy vs 10 x 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 x 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 x 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.

[Palliative radiotherapy of bone metastases. A retrospective analysis of 176 patients]. / Palliative Strahlentherapie von Knochenmetastasen. Eine retrospective Analyse von 176 Patienten.

BACKGROUND: The effect of the palliative irradiation of bone metastases was explored in this retrospective analysis. The spectrum of primary tumor sites, the localization of the bone metastases and the fractionation schedules were analyzed with regard to palliation discriminating total, partial and complete pain response. PATIENTS AND METHODS: One hundred seventy-six patients are included in this retrospective quantitative study from April 1992 to November 1993. Two hundred fifty-eight localizations of painful bone metastases were irradiated. The percentage of bone metastases of the total irradiated localizations in our department of radiotherapy in the Charité-Hospital, the primary tumor sites, the localizations and the different fractionation schedules were explored. The total, partial and complete pain response was analyzed in the most often used fractionation schedules and by primary tumor sites. RESULTS: Eight per cent of all irradiated localizations in the observation period were bone metastases. There were irradiated bone metastases of 21 different tumor sites. Most of the primary tumor sites were breast cancer (49%), lung cancer (6%) and kidney cancer (6%). The most frequent site of metastases was the vertebral column (52%). The most often used fractionation schedules were: 4 x 5 Gy (32%), 10 x 3 Gy (18%), 6 x 5 Gy (9%), 7 x 3 Gy (7%), 10 x 2 Gy (5%) and 2 x 8 Gy. The total response rates in this fractionation schedules were 72%, 79%, 74%, 76%, 75% and 72%, the complete response rates were 35%, 32%, 30%, 35%, 33% and 33%. There were no significant differences between the most often irradiated primary tumor sites, the most frequent localizations and the palliation with regard to total, partial and complete pain response. CONCLUSION: There are no differences between the different fractionation schedules with regard to the pain effect of bone metastases. A palliation is ensured in 75% of all cases with a partial response of 42% and complete response of 33%. With regard to pain response these results do not justify a recommendation for a standard fractionation schedule. Current fractionation schedules such as 10 x 3 Gy for 2 weeks or 5 x 4 Gy for 1 week should be used. Another point is the recalcification in the palliative treatment of bone metastases in patients with better prognosis. The recalcification is the basis for stabilization and prevention of fractures. This aspect should be explored in prospective studies.

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, Wilcoxon's 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.

[Comparison of different 3-dimensional irradiation techniques in local radiotherapy of prostatic carcinoma]. / Vergleich unterschiedlicher dreidimensionaler Bestrahlungstechniken bei der lokalen Strahlentherapie des Prostatakarzinoms.

PURPOSE: Four different three-dimensional planning techniques for localized radiotherapy of prostate cancer were compared with regard to dose homogeneity within the target volume and dose to organs at risk, dependent upon tumor stage. PATIENTS AND METHODS: Six patients with stage T1, 7 patients with stage T2 and 4 patients with stage T3 were included in this study. Four different 3D treatment plans (rotation, 4-field, 5-field and 6-field technique) were calculated for each patient. Dose was calculated with the reference point at the isocenter (100%). The planning target volume was encompassed within the 95% isodose surface. All the techniques used different shaped portal for each beam. Dose volume histograms were created and compared for the planning target volume and the organs at risk (33%, 50%, 66% volume level) in all techniques. RESULTS: The 4 different three-dimensional planning techniques revealed no differences concerning dose homogeneity within the planning target volume. The dose volume distribution at organs at risk show differences between the calculated techniques. In our study the best protection for bladder and rectum in stage T1 and T2 was achieved by the 6-field technique. A significant difference was achieved between 6-field and 4-field technique only in the 50% volume of the bladder (p = 0.034), between the 6-field and rotation technique (all volume levels) and between 5-field and rotation technique (all volume levels). In stage T1, T2 6-field and 4-field technique in 50% (p = 0.033) and 66% (p = 0.011) of the rectum volume. In stage T3 a significant difference was not observed between the 4 techniques. The best protection of head of the femur was achieved by the rotation technique. CONCLUSION: In the localized radiotherapy of prostate cancer in stage T1 or T2 the best protection for bladder and rectum was achieved by a 3D-planned conformal 6-field technique. If the seminal vesicles have been included in the target volume and in the case of large planning target volume other techniques should be taken for a better protection for organs at risk e. g. a 3D-planned 4-field technique box technique.

Comparison of conventional and virtual simulation for radiation treatment planning of malignant lymphoma.

PURPOSE: The exact coverage of the lymph nodes and optimal shielding of the organs at risk are necessary for patients with Hodgkin's disease or malignant lymphoma to guarantee a high cure rate and a low rate of late effects for normal tissue. The purpose of this study was to compare conventional simulation and blocking with virtual simulation in terms of coverage of the target volume and shielding of the organs at risk in this highly curative patient group. PATIENTS AND METHODS: In 10 patients diagnosed with Hodgkin's disease and 5 patients with a Non-Hodgkin lymphoma radiation treatment planning for a mantle field or para-aortic field with inclusion of the spleen was performed in a conventional manner and with virtual simulation. With conventional technique, irradiation portals were defined during fluoroscopy and shielding of the organs at risk was drawn onto the simulation films, based on the information from previous X-ray films, CT or MRI scans. For virtual simulation, contouring of the target volumes and organs at risk (e.g. the kidneys) and the definition of the irradiation portals were performed with the AcQSim software package on a VoxelQ workstation (Picker Inc.) This was done in a beam's eye view environment on a currently driven CT scan in the treatment position. Both irradiation portals were compared in terms of coverage of the target volume and shielding of the organs at risk. RESULTS: Planning of a mantle field in the conventional way resulted in an incomplete coverage of the right hilus in 4/15 cases and of the left in 1/15 cases, respectively. The spleen and the spleen hilus were not covered completely in 5/15 and 6/15 cases, respectively. The left kidney was adequately shielded in only two thirds (10/15) of the conventionally planned fields. The planning time required for virtual simulation was reduced for the patient, but was increased for the physician because of the more time consuming contouring procedure compared to conventional simulation. CONCLUSIONS: Virtual simulation based on CT scans for radiation treatment planning of malignant lymphoma gives more information about soft tissue structures than conventional treatment planning. Therefore, it allows a more precise coverage of the target volumes and better shielding of the organs at risk. However, the time required for the whole procedure is increased. This is justified because of the often highly curative intention when treating this group of patients.

High-dose rate interstitial with external beam irradiation for localized prostate cancer--results of a prospective trial.

PURPOSE: A prospective phase II trial was carried out to test the feasibility and effectiveness of a combined interstitial with external beam radiotherapy approach for localized prostate cancer. MATERIALS AND METHODS: Between October 1992 and December 1994, 82 evaluable patients were treated. T2 and T3 tumours, according to the AJCC classification system of 1992, were found in 21 and 61 cases, respectively. The median follow-up was 24 months; three patients were lost during follow-up. All of the patients were pathologically proven to be node-negative by laparoscopic node dissection of the fossa obturatoria region. A dose of 9 Gy a week was prescribed during the first and second weeks of treatment (10 Gy each week from October 1992 to December 1993) interstitially with high-dose rate Iridium-192 brachytherapy to the prostate and tumour extension beyond the capsule. External beam four-field box irradiation was then given to the prostate to a dose of 45 Gy/25 fractions (40 Gy/20 fractions from October 1992 to December 1993). RESULTS: Before starting treatment, a PSA value of > or =10 ng/ml was found in 64.6% (53/82) of patients with a median PSA of 14.0 ng/ml. The median PSA 3, 12 and 24 months after completion of therapy was 1.20, 0.78 and 0.70 ng/ml, respectively. The PSA value was < 1.0 ng/ ml in 52.9% of patients at 2 years. Negative punch biopsies 12 and 24 months after therapy were observed in 69.8% (44/63) and 73. 1% (38/ 52) of patients, respectively. A positive biopsy combined with a PSA value of > 1.0 ng/ml was considered as local failure. The local tumour control rate was 79.5% at 2 years. Acute side-effects were not increased relative to external beam irradiation alone. Severe side-effects were observed in three patients (two of the three patients had additional risk factors (colitis ulcerosa and diabetes mellitus)); they developed rectourethral fistulae requiring colostomy after biopsies from the anterior rectal wall. CONCLUSION: The described method is feasible and well tolerable. The three complications observed were not caused by irradiation alone. Biopsies from the anterior rectal wall after definitive high-dose radiotherapy for prostate cancer have to be seen as obsolete. The rate of negative prostate biopsies of 73.1% after 24 months represents an encouraging result.

[Virtual simulation. First clinical results in patients with prostate cancer]. / Virtuelle Simulation. Erst klinische Ergebnisse bei Patienten mit Prostatakarzinom.

AIM: Investigation of options of virtual simulation in patients with localized prostate cancer. PATIENTS AND METHODS: Twenty-four patients suffering from prostate cancer were virtual simulated. The clinical target volume was contoured and the planning target volume was defined after CT scan. The isocenter of the planning target volume was determined and marked at patient's skin. The precision of patients marking was controlled with conventional simulation after physical radiation treatment planning. RESULTS: Mean differences of the patient's mark revealed between the 2 simulations in all room axes around 1 mm. The organs at risk were visualized in the digital reconstructed radiographs. CONCLUSIONS: The precise patient's mark of the isocentre by virtual simulation allows to skip the conventional simulation. The visualisation of organs at risk leeds to an unnecessarily of an application of contrast medium and to a further relieve of the patient. The personal requirement is not higher in virtual simulation than in conventional CT based radiation treatment planning.