Johann H. Karstens

Intensified Chemotherapy and Dose-Reduced Involved-Field Radiotherapy in Patients With Early Unfavorable Hodgkin's Lymphoma: Final Analysis of the German Hodgkin Study Group HD11 Trial

PURPOSE Combined-modality treatment consisting of four to six cycles of chemotherapy followed by involved-field radiotherapy (IFRT) is the standard of care for patients with early unfavorable Hodgkins lymphoma (HL). It is unclear whether treatment results can be improved with more intensive chemotherapy and which radiation dose needs to be applied. PATIENTS AND METHODS Patients age 16 to 75 years with newly diagnosed early unfavorable HL were randomly assigned in a 2 × 2 factorial design to one of the following treatment arms: four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) + 30 Gy of IFRT; four cycles of ABVD + 20 Gy of IFRT; four cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP(baseline)) + 30 Gy of IFRT; or four cycles of BEACOPP(baseline) + 20 Gy of IFRT. RESULTS With a total of 1,395 patients included, the freedom from treatment failure (FFTF) at 5 years was 85.0%, overall survival was 94.5%, and progression-free survival was 86.0%. BEACOPP(baseline) was more effective than ABVD when followed by 20 Gy of IFRT (5-year FFTF difference, 5.7%; 95% CI, 0.1% to 11.3%). However, there was no difference between BEACOPP(baseline) and ABVD when followed by 30 Gy of IFRT (5-year FFTF difference, 1.6%; 95% CI, -3.6% to 6.9%). Similar results were observed for the radiotherapy question; after four cycles of BEACOPP(baseline), 20 Gy was not inferior to 30 Gy (5-year FFTF difference, -0.8%; 95% CI, -5.8% to 4.2%), whereas inferiority of 20 Gy cannot be excluded after four cycles of ABVD (5-year FFTF difference, -4.7%; 95% CI, -10.3% to 0.8%). Treatment-related toxicity occurred more often in the arms with more intensive therapy. CONCLUSION Moderate dose escalation using BEACOPP(baseline) did not significantly improve outcome in early unfavorable HL. Four cycles of ABVD should be followed by 30 Gy of IFRT.

Prognostic Factors for Local Control and Survival After Radiotherapy of Metastatic Spinal Cord Compression

PURPOSE To evaluate potential prognostic factors for local control and survival after radiotherapy of metastatic spinal cord compression (MSCC). PATIENTS AND METHODS The following potential prognostic factors were investigated retrospectively in 1,852 patients irradiated for MSCC: age, sex, performance status, primary tumor, interval between tumor diagnosis and MSCC (< or = 15 v > 15 months), number of involved vertebrae (one to two v > or = three), other bone metastases, visceral metastases, pretreatment ambulatory status, time of developing motor deficits before radiotherapy (faster, 1 to 14 v slower, > 14 days), and radiation schedule (short-course v long-course radiotherapy). RESULTS On univariate analysis, improved local control of MSCC was associated significantly with favorable histology (breast cancer, prostate cancer, lymphoma/myeloma), no visceral metastases, and long-course radiotherapy. On multivariate analysis, absence of visceral metastases and radiation schedule maintained significance. On univariate analysis, improved survival was associated significantly with female sex, favorable histology, no visceral or other bone metastases, good performance status, being ambulatory before radiotherapy, longer interval between tumor diagnosis and MSCC, and slower development of motor deficits before radiotherapy. Long-course radiotherapy showed a trend. On multivariate analysis, histology, visceral metastases, other bone metastases, ambulatory status before radiotherapy, interval between tumor diagnosis and MSCC, and time of developing motor deficits maintained significance. CONCLUSION Poorer local control after radiotherapy for MSCC is associated with visceral metastases and short-course radiotherapy. Long-course radiotherapy seems preferable for patients with more favorable prognoses, given that these patients may live long enough to develop MSCC recurrences. Long-term survival after radiotherapy for MSCC may be predicted if several prognostic factors are considered.

Positron emission tomography with 11C-acetate and 18F-FDG in prostate cancer patients

Visualisation of primary prostate cancer, its relapse and its metastases is a clinically relevant problem despite the availability of state-of-the-art methods such as CT, MRI, transrectal ultrasound and fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET). The aim of this study was to evaluate the efficacy of carbon-11 acetate and 18F-FDG PET in the detection of prostate cancer and its metastases. Twenty-five patients were investigated during the follow-up of primary prostate cancer, suspected relapse or metastatic disease using 11C-acetate PET; 15 of these patients were additionally investigated using 18F-FDG PET. Fourteen patients were receiving anti-androgen treatment at the time of the investigation. Lesions were detected in 20/24 (83%) patients using 11C-acetate PET and in 10/15 (75%) patients using 18F-FDG PET. Based on the results of both PET scans, one patient was diagnosed with recurrent lung cancer. Median 18F-FDG uptake exceeded that of 11C-acetate in distant metastases (SUV =3.2 vs 2.3). However, in local recurrence and in regional lymph node metastases, 11C-acetate uptake (median SUVs =2.9 and 3.8, respectively) was higher than that of 18F-FDG (median SUVs =1.0 and 1.1, respectively). A positive correlation was observed between serum PSA level and both 11C-acetate uptake and 18F-FDG uptake. 11C-acetate seems more useful than 18F-FDG in the detection of local recurrences and regional lymph node metastases. 18F-FDG, however, appears to be more accurate in visualising distant metastases. There may be a role for combined 11C-acetate/18F-FDG PET in the follow-up of patients with prostate cancer and persisting or increasing PSA.

Final results of a prospective study of the prognostic value of the time to develop motor deficits before irradiation in metastatic spinal cord compression.

PURPOSE Metastatic spinal cord compression often requires urgent treatment selection, which could be facilitated by strong prognostic factors. Because only the type of primary tumor and pretreatment ambulatory status are known as prognostic factors for functional outcome, we investigated the prognostic value of the time of motor deficit development before radiotherapy (RT). METHODS AND MATERIALS Ninety-eight patients were included between November 1998 and April 2000. Three subgroups were formed, according to time of motor deficit development before RT: 1-7 days (n = 31), 8-14 days (n = 31), and >14 days (n = 36). Ambulatory rates and motor function were evaluated for < or =24 weeks after RT. In a multivariate analysis, all three prognostic factors and radiation parameters were included. RESULTS In the >14-day subgroup, improvement occurred significantly (p < 0.001) more often than in the other subgroups (86% vs. 29% and 10%) and the posttreatment ambulatory rate was significantly higher (86% vs. 55% and 35%, p = 0.026). Multivariate analysis revealed the time of development of motor deficits before RT to be the strongest prognostic factor. CONCLUSION Functional outcome is significantly better with slower development of motor deficits before RT. This new, independent, prognostic factor must be considered in future trials aiming to define an optimal RT schedule.

Matched Pair Analysis Comparing Surgery Followed By Radiotherapy and Radiotherapy Alone for Metastatic Spinal Cord Compression

PURPOSE The appropriate treatment for MSCC is controversial. A small randomized trial showed that decompressive surgery followed by radiotherapy was superior to radiotherapy alone. That study was limited to highly selected patients. Additional studies comparing surgery plus radiotherapy to radiotherapy could better clarify the role of surgery. METHODS Data from 108 patients receiving surgery plus radiotherapy were matched to 216 patients (1:2) receiving radiotherapy alone. Groups were matched for 11 potential prognostic factors and compared for post-treatment motor function, ambulatory status, regaining ambulatory status, local control, and survival. Subgroup analyses were performed for patients receiving adequate surgery (direct decompressive surgery plus stabilization of involved vertebrae), patients receiving laminectomy, patients with solid tumors, patients with solid tumors receiving adequate surgery, and patients with solid tumors receiving laminectomy. RESULTS Improvement of motor function occurred in 27% of patients after surgery plus radiotherapy and 26% after radiotherapy alone (P = .92). Post-treatment ambulatory rates were 69% after surgery plus radiotherapy and 68% after radiotherapy alone (P = .99). Of the nonambulatory patients, 30% and 26%, respectively, (P = .86) regained ambulatory status after treatment. One-year local control rates were 90% after surgery plus radiotherapy and 91% after radiotherapy alone (P = .48). One-year overall survival rates were 47% and 40%, respectively (P = .50). The subgroup analyses did not show significant differences between both groups. Surgery-related complications occurred in 11% of patients. CONCLUSION In this study, the outcomes of the end points evaluated after radiotherapy alone appeared similar to those of surgery plus radiotherapy. A new randomized trial comparing both treatments is justified.

Nijmegen Breakage Syndrome mutations and risk of breast cancer.

Mutations in the NBS1 gene have been identified as disease‐causing mutations in patients with Nijmegen Breakage Syndrome (NBS), but their clinical impact on breast cancer susceptibility has remained uncertain. We determined the frequency of 2 NBS mutations, 657del5 and R215W, in two large series of breast cancer cases and controls from Northern Germany and from the Republic of Belarus. The 5‐bp‐deletion 657del5 was identified in 15/1,588 cases (0.9%) from Belarus and in 1/1,076 cases (0.1%) from Germany but in only 1/1,014 population controls from Belarus and 0/1017 German controls (p < 0.01). The missense substitution R215W was observed in 9/1,588 Byelorussian and 9/1,076 German patients (0.6% and 0.8%, respectively) but was also present in 5/1,014 Byelorussian and 2/1,017 German control individuals (adjusted OR = 1.9, 95%CI 0.8–4.6, p = 0.18). Studies of lymphoblastoid cell lines revealed that NBS1/p95 protein levels were reduced to 70% in cells from a heterozygous breast cancer patient carrying R215W and to 15% in cells from a NBS patient compound heterozygous for 657del5/R215W suggesting that the R215W substitution may be associated with protein instability. Levels of radiation‐induced phosphorylation of Nbs1/p95(Ser343) were reduced to 60% and 35% of wildtype, respectively. Neither age at diagnosis nor family history of breast cancer differed significantly between carriers and noncarriers of NBS mutations. The combined data are in line with an about 3‐fold increase in breast cancer risk for female NBS heterozygotes (OR 3.1; 95%CI 1.4–6.6) and indicate that the 657del5 deletion and perhaps the R215W substitution contribute to inherited breast cancer susceptibility in Central and Eastern Europe.

Association of two mutations in the CHEK2 gene with breast cancer

The 1100delC mutation of the cell cycle checkpoint kinase 2 (CHEK2) gene confers an increased risk for breast cancer, but the clinical impact of other CHEK2 gene variants remains unclear. We determined the frequency of two functionally relevant CHEK2 gene mutations, I157T and IVS2+1G > A, in two large series of breast cancer cases and controls from two independent populations. Our first series consisted of a hospital‐based cohort of 996 German breast cancer cases and 486 population controls, and the second series consisted of 424 breast cancer patients and 307 population controls from the Republic of Belarus. The missense substitution I157T was identified in 22/996 cases (2.2%) vs. 3/486 controls (0.6%; OR = 3.6, 95% CI 1.1–12.2, p = 0.044) in the German population and in 24/424 cases (5.7%) vs. 4/307 controls (1.3%; OR = 4.5, 95% CI 1.6–13.2, p = 0.005) in the Byelorussian cohorts. The splicing mutation IVS2+1G > A was infrequent in both populations, being observed in 3/996 German and 4/424 Byelorussian patients (0.3% and 0.9%, respectively) and in 1/486 German controls (0.2%; adjusted OR = 4.0, 95% CI 0.5–30.8, p = 0.273). Heterozygous CHEK2 mutation carriers tended to be diagnosed at an earlier age in both populations, but these differences did not reach statistical significance. Family history of breast cancer did not differ between carriers and noncarriers. Our data indicate that the I157T allele, and possibly the IVS2+1G > A allele, of the CHEK2 gene contribute to inherited breast cancer susceptibility.

Outcome After Radiotherapy Alone for Metastatic Spinal Cord Compression in Patients With Oligometastases

PURPOSE To investigate outcome and prognosis of metastatic spinal cord compression (MSCC) patients with oligometastatic disease treated with radiotherapy alone. PATIENTS AND METHODS Oligometastatic disease was defined as involvement of three or fewer vertebrae and lack of other bone or visceral metastases. Five hundred twenty-one patients with oligometastatic disease and MSCC were evaluated for functional outcome, ambulatory status, local control of MSCC, and survival. Furthermore, seven potential prognostic factors were investigated. RESULTS Motor function improved in 40% (n = 207), remained stable in 54% (n = 279), and deteriorated in 7% (n = 35) of patients. Fifty-eight (54%) of 107 nonambulatory patients became ambulatory, and 388 (94%) of 414 ambulatory patients remained ambulatory. Improved functional outcome was significantly associated with tumor type and slower development of motor deficits (> 14 days). Local control at 1, 2, and 3 years was 92%, 88%, and 78%, respectively. Improved local control was significantly associated with long-course radiotherapy. Survival at 1, 2, and 3 years was 71%, 58%, and 50%, respectively. Better survival was significantly associated with tumor type, ambulatory status, slower development of motor deficits, and long-course radiotherapy. Patients who developed motor deficits slowly (onset > 14 days before initiating treatment) were further analyzed. In this subgroup, the best results were observed for myeloma/lymphoma and breast cancer patients. No patient had progression of motor deficits. One hundred percent (myeloma/lymphoma) and 99% (breast cancer) of patients were ambulatory after radiotherapy. One-year local control was 100% and 98%, 1-year survival was 94% and 89%. CONCLUSION Given the limitations of a retrospective review, improved outcome of patients with oligometastatic MSCC was associated with myeloma/lymphoma and breast cancer, slower development of motor deficits, and a more prolonged course of radiation.

Long-term results of interstitial brachytherapy (LDR-Brachytherapy) in the treatment of patients with prostate cancer.

Permanent interstitial brachytherapy represents the most conformal form of radiation therapy of the prostate and the number of patients with prostate cancers treated with permanent radioactive implants is increasing world wide. In the meanwhile long-term data on tumor control and treatment morbidity become available. Biochemical and clinical tumor control appears to be as effective as after radical prostatectomy or external beam radiation therapy in early prostate cancer. The risk of postreatment urinary incontinence and bowel dysfunction is low and erectile function can be preserved in the majority of patients. However, prostate brachytherapy requires a careful selection of patients as pretreatment factors predict for long-term outcome. The need for combined modality approaches in intermediate and high-risk patients remains controversely discussed. The continous refinement of intraoperative planning techniques and the elucidation of the etiology of urinary, sexual, and bowel dysfunction should result in further improvements in biochemical outcomes and decreased morbidity. Improved and standardized postimplantation evaluation will make outcome data more reliable and comparable.

A Score Predicting Posttreatment Ambulatory Status in Patients Irradiated for Metastatic Spinal Cord Compression

PURPOSE To create a scoring system to predict ambulatory status after radiotherapy (RT) for metastatic spinal cord compression (MSCC). METHODS AND MATERIALS On the basis of a multivariate analysis of 2096 MSCC patients, a scoring system was developed. This included the five prognostic factors significantly associated with post-RT ambulatory status: primary tumor type, interval between tumor diagnosis and MSCC, visceral metastases, motor function before RT, and time developing motor deficits before RT. The score for each factor was determined by dividing the post-RT ambulatory rate (as a percentage) by 10. Total scores represented the sum of the scores for each factor and ranged between 21 and 44 points. Patients were divided into five groups according to this score. RESULTS The post-RT ambulatory rates were 6% (24 of 389) for patients with scores of </=28 points, 44% (121 of 278) for those with 29-31 points, 70% (212 of 303) for those with 32-34 points, 86% (315 of 266) for those with 35-37 points, and 99% (750 of 760) for those with >/=38 points. The 3-month survival rates were 29%, 62%, 77%, 84%, and 98%, respectively. The 6-months survival rates were 6%, 31%, 42%, 61%, and 93%, respectively. CONCLUSIONS Because patients with scores of </=28 points had poor functional outcome after RT and extraordinarily poor survival rates, short-course RT to decrease pain or best supportive care may be considered. Patients with scores of 29-37 points should be considered surgical candidates, because RT-alone results were not optimal. Patients with scores of >/=38 points seem to have excellent results with RT alone.