Mary Gospodarowicz

Report of an International Workshop to Standardize Baseline Evaluation and Response Criteria for Primary CNS Lymphoma

Standardized guidelines for the baseline evaluation and response assessment of primary CNS lymphoma (PCNSL) are critical to ensure comparability among clinical trials for newly diagnosed patients. The relative rarity of this tumor precludes rapid completion of large-scale phase III trials and, therefore, our reliance on the results of well-designed phase II trials is critical. To formulate this recommendation, an international group of experts representing hematologic oncology, medical oncology, neuro-oncology, neurology, radiation oncology, neurosurgery, and ophthalmology met to review current standards of reporting and to formulate a consensus opinion regarding minimum baseline evaluation and common standards for assessing response to therapy. The response guidelines were based on the results of neuroimaging, corticosteroid use, ophthalmologic examination, and CSF cytology. A critical issue that requires additional study is the optimal method to assess the neurocognitive impact of therapy and address the quality of life of PCNSL survivors. We hope that these guidelines will improve communication among investigators and comparability among clinical trials in a way that will allow us to develop better therapies for patients.

Radiation therapy for pituitary adenoma: Treatment outcome and prognostic factors

PURPOSEnRadiation therapy is often an integral part of postoperative treatment in patients with nonfunctional pituitary adenomas. The Princess Margaret Hospital (PMH) experience was reviewed and analyzed to establish the role of radiation therapy in local control relative to its complications, and to see if subgroups of patients with a greater or lesser risk of recurrence postsurgery can be defined.nnnMETHODS AND MATERIALSnRecords of 160 patients with nonfunctional pituitary adenoma treated between 1972 and 1986 were reviewed retrospectively. The review focused on 128 patients treated with surgery and postoperative radiation as initial therapy. The median total dose was 45 Gy. Local tumor control was defined as lack of progression or recurrence of adenoma as assessed clinically and by imaging studies. The following factors were analyzed for prognostic significance in local tumor control: age, sex, direction of tumor extension, radiation dose, and preoperative tumor size as reflected by the radiation field size. Complications including hypopituitarism and second tumors were analyzed. Hypopituitarism was defined as requirement for permanent hormone replacement therapy.nnnRESULTSnWith a median follow-up duration of 8.3 years, the 10-year actuarial local control rate was 87% for the entire 160 patients and 91% for the 128 patients given postoperative radiation as initial treatment. For the 29 patients referred for treatment of recurrent tumor, the 10-year local control rate was 78%. Prognostic factors for local control identified in univariate analysis included age (p = 0.005) and radiation field size (p = 0.0001). Older patients and those with larger tumors requiring large radiation portals were less likely to achieve durable local control. These two factors remained significant in a multivariate analysis (p < 0.005). The major complication, hypopituitarism requiring hormonal replacement with thyroxine, glucocorticoid, and sex hormone was observed to date in 65% (100 out of 155), 68% (105 out of 154), and 67% (85 out of 127) of evaluable patients, respectively. Radiation was the contributing cause of the hypopituitarism in only 23%, 16%, and 13%, respectively. There were no cases of brain necrosis or radiation damage to the optic pathways. Two patients developed a fatal in-field glioma of the brain stem at 10 and 15 years following radiation.nnnCONCLUSIONnPostoperative external beam radiation therapy is highly effective in preventing recurrence of hormonally inactive pituitary adenomas. Hypopituitarism is commonly observed, but radiation can only be incriminated as the contributing cause in approximately one-fifth of the cases. Treatment of patients at the time of recurrence gave comparable local control rates to those irradiated initially. Favorable patients (age < or = 50, with small tumors removed totally) probably can be safely observed postoperatively with radiation reserved for recurrence.

SEMINOMA OF THE TESTIS: RESULTS OF TREATMENT AND PATTERNS OF FAILURE AFTER RADIATION THERAPY

Four hundred and forty-four patients with the histological diagnosis of pure seminoma were treated at The Princess Margaret Hospital between 1958 and 1976. Using the Walter Reed Hospital staging classification, 338 patients (76.1%) were Stage I, 86 (19.4%) were Stage II, and 20 (4.7%) were Stage III. The 5 year actuarial survival rate (5 yr Sa) for all stages was 87%, and for Stages I, II and III: 94%, 74% and 32% respectively. In Stage II the 5-year Sa was significantly worse when palpable abdominal disease was present (62%, vs 87% when it was absent, p less than .02). Prophylactic mediastinal irradiation was not used for patients with Stage II disease. None of 40 Stage II patients without palpable abdominal disease recurred in the non-irradiated mediastinum. Ten of 46 Stage II patients with palpable abdominal disease recurred in the mediastinum; 7 of the 10 were cured with mediastinal irradiation at the time of relapse. Prophylactic mediastinal irradiation appears unnecessary in Stage II patients. The Stage III category includes a subgroup of patients who were curable with radiation therapy:L 5/6 with supradiaphragmatic nodal disease without palpable abdominal or visceral disease were cured. Exploration of new treatment methods appears indicated for the salvage of patients recurring in sites other than the mediastinum or supraclavicular fossa and for patients presenting with visceral disease.

ROLE OF RADIATION THERAPY IN CLINICAL HORMONALLY-ACTIVE PITUITARY ADENOMAS

BACKGROUND AND PURPOSEnThe outcome following radiation therapy (RT) of hormonally-active pituitary adenomas was assessed. The purpose of this analysis was to determine the control rate after radiation, identify any prognostic factors and evaluate the late toxicity.nnnMATERIALS AND METHODSnFrom 1972 to 1986, 145 patients received RT for hormonally-active pituitary adenomas. The median age was 39 years (range 15-76), with 81 males and 64 females. There were 52 patients with acromegaly, 64 with prolactinoma, and 29 with Cushings disease. The median follow-up was 7.3 years. RT was given as primary treatment in 17 patients, after initial surgery in 65 patients, and as part of salvage therapy in 63 patients. The median total dose was 50 Gy (daily fraction: 2 Gy). Tumor control was defined as normalization of basal hormonal level and lack of progression of adenoma assessed by imaging studies. The following factors were analyzed for prognostic significance in tumor control: age, sex, tumor type, direction of tumor extension, radiation dose, and radiation field size.nnnRESULTSnThe 10-year actuarial proportion of patients with persistent elevated hormone level were 61% following RT alone, and 44% with the addition of medical management. The progression-free rate was 96% at 10 years. Of the 20 deaths, three patients died with uncontrolled pituitary adenoma and three died of treatment complications. The actuarial 10-year overall and cause-specific survival rates were 86% and 97%. The actuarial rates of radiation-induced hypopituitarism were 35%, 22% and 22% at 10 years for thyroid, glucocorticoid and gonadal functions, respectively. None of the factors examined were found to be significant predictors of tumor control.nnnCONCLUSIONSnPost-operative external beam RT is highly effective in preventing recurrence of space-occupying effects of hormonally-active pituitary adenomas. However, long-term biochemical remission is observed only in approximately 40% of patients (at 10 years), with an additional 20% requiring medical therapy. Malignancies of the CNS can develop as an infrequent late event.

Magnetic resonance imaging (MRI) for localization of the prostatic apex: comparison to computed tomography (CT) and urethrography

BACKGROUND AND PURPOSEnIt is necessary to include the entire prostate in the high dose treatment volume when planning radical radiation for patients with prostate cancer. We prospectively compared magnetic resonance imaging (MRI) to computed tomography (CT) and urethrography as means of localizing the prostatic apex.nnnMATERIALS AND METHODSnThirty patients with clinically localized prostate cancer had a sagittal T2-weighted MRI scan and a conventional axial CT scan performed in the treatment position prior to the start of radiotherapy. Twenty of these patients had a static retrograde urethrogram performed at simulation. The position of the MRI and CT apices were localized independently by two radiation oncologists. In addition, the MRI apex was localized independently by a diagnostic radiologist. The urethrogram apex, defined as the tip of the urethral contrast cone, was easily identified and was therefore localized by only one observer.nnnRESULTSnThere was good interobserver agreement in the position of the MRI apex. Interobserver agreement was significantly better with MRI than with CT. There were no systematic differences in the position of the MRI and CT apices. However, the MRI apex was located significantly above and behind the urethrogram apex. There was poor correlation between MRI and CT and between MRI and urethrogram in the height of the apex above the ischial tuberosities. There was 83% agreement between MRI and CT and 80% agreement between MRI and urethrogram in the identification of patients with a low-lying apex. The apex, as determined by MRI, was <2 cm above the ischial tuberosities and therefore potentially under-treated in 17% of the patients.nnnCONCLUSIONSnMRI is superior to CT and urethrography for localization of the prostatic apex. All patients undergoing radiotherapy for prostate cancer should have localization of the apex using MRI or a technique of equal precision to assure adequate dose delivery to the entire prostate and to minimize the unnecessary irradiation of normal tissues.

The extranodal lymphomas

Primary extranodal lymphomas, a heterogeneous group of diseases of diverse etiology, pathogenesis, pattern of presentation and outcome, account for up to 20% of all malignant lymphomas. The gastrointestinal tract is the most common presenting site, but virtually every extranodal location has been reported. Most are B-cell, diffuse large-cell type; follicular histology is less common. In low-grade, particularly mucosa-associated lymphoid tissue lymphoma that tends be localized and is associated with an excellent prognosis, radiation therapy offers cure with minimal side effects. These include gastric, salivary gland, Waldeyers ring and thyroid, orbital, low-grade lymphomas of the breast, and other less common sites. The intermediate-grade lesions of diffuse large-cell and B-lineage commonly occur in Waldeyers ring, paranasal sinus, thyroid, breast, intestine, bone and are highly curable with combined modality therapy. Less common brain, testicular, ocular, T-cell tumors, including intestinal, nasal, and cutaneous lymphomas, currently evade cure and thus deserve special consideration. Many extranodal lymphomas are indolent and associated with a prolonged survival; knowledge of factors responsible for transformation to more aggressive forms of disease, ultimate dissemination, and potential curability of these disorders is limited. Accordingly, therapeutic trials focused on short-term outcomes are clearly of limited value for many of the indolent lymphomas. The future approach to management of extranodal lymphomas may have more basis in the etiology and pathogenesis of these disorders than purely on histological appearance and anatomic extent. Better understanding of the immune response and its relation to lymphoproliferative disorders may ultimately lead to a lesser focus on ablative cytotoxic therapies and an increased emphasis on specific etiological determinants and the control of aberrant immune response.

Assessment of endpoints for clinical trials for localized prostate cancer

OBJECTIVESnThe AUA Practice Guidelines Panel convened to address the issue of appropriate endpoints for assessment of treatment modalities for localized carcinoma of the prostate.nnnMETHODSnA review of the literature and the design of existing clinical trials produced a consensus, which was presented to and critiqued by the members of the general conference.nnnRESULTSnThe pitfalls associated with identification of local failure endpoints were discussed, and the more accurate endpoints of freedom from metastatic progression and overall survival were recognized. The strict definition that must be fulfilled for intermediate endpoints to become surrogates for metastasis free and/or survival endpoints was stressed. For more efficient and rapid conduct of future clinical trials, the urgent need to validate such surrogate endpoints by evaluation in randomized control trials is obvious. PSA, while an indicator of disease activity and a critical marker for estimating disease progression or regression in response to therapy, is not a surrogate for metastasis free or overall survival.nnnCONCLUSIONnUntil surrogate endpoints are validated, the committee has evaluated the endpoints in current use, reviewed their limitations, and stressed the importance of quality-of-life assessment together with the traditional endpoint assessment.

Primary and secondary bone lymphomas.

Recent studies have contributed to the enhancement of clinical and molecular knowledge on bone lymphomas, a group of rare malignancies with particular characteristics. Nevertheless, several questions remain unanswered and the level of evidence supporting some diagnostic and therapeutic decisions remains low. Currently, three different forms of bone lymphomas can be distinguished: the primary bone lymphoma, consisting of a single bone lesion with or without regional lymphadenopathies; the polyostotic lymphoma, consisting of multifocal disease exclusively involving the skeleton; and the disseminated lymphoma with secondary infiltration of the skeleton. The first two forms exhibit a good prognosis, requiring treatments similar to those commonly used for nodal lymphomas of the same category, but several issues regarding the role of surgery and local control of the disease, the sequence of treatment, radiation volumes and doses, management of pathological fractures and prevention of late sequelae deserve particular attention. Due to its rarity, prospective trials exclusively focused on bone lymphomas appear unrealistic, thus, critical revision of our own experience and analyses of large cumulative series as well as molecular studies on archival cases remain valid alternatives to improve our knowledge on this obscure lymphoproliferative malignancy. The present review is based on the analysis of the largest available database of bone lymphomas established under the sponsorship of the International Extranodal Lymphoma Study Group (IELSG) as well as on the critical revision of related literature. We provide recommendations for diagnosis, staging, treatment, and response assessment of these patients in everyday practice as well as for the management of special conditions like pathological fractures, indolent forms and central nervous system prophylaxis.

Clinical features, management and prognosis of multifocal primary bone lymphoma: A retrospective study of the international extranodal lymphoma study group (the IELSG 14 study)

‘Multifocal bone lymphoma’ or ‘polyostotic lymphoma’ is a neoplasm with exclusive multifocal involvement of the skeleton, without affecting lymph nodes or other soft tissues. Knowledge on this uncommon condition is limited because the related literature is sparse and fragmentary. We reviewed cases of multifocal bone diffuse large B‐cell lymphoma (MB‐DLBCL) registered in a clinico‐pathological database of the International Extranodal Lymphoma Study Group that includes 499 cases of bone lymphoma. Clinical features, management and prognosis of 37 MB‐DLBCL patients and 63 ‘controls’ (stage‐IV DLBCL and skeletal involvement) were analysed. Presentation and treatment of MB‐DLBCL and controls were identical. At a median follow‐up of 52 months (10–189), MB‐DLBCL patients exhibited a significantly better response rate (92% vs. 65%; P = 0·002), progression‐free survival (5‐year: 56 ± 9% vs. 34 ± 6%; P = 0·003) and overall survival (5‐year: 74 ± 8% vs. 36 ± 7%; P = 0·002). Among MB‐DLBCL patients, the use of post‐chemo radiotherapy was associated with better overall survival (5‐year: 83 ± 12% vs. 55 ± 16%; P = 0·003). Two MB‐DLBCL patients (5·4%) with spine and skull involvement experienced central nervous system (CNS) relapse. Thus, MB‐DLBCL patients exhibit a significantly better prognosis compared to patients with advanced‐stage DLBCL, and should be treated with conventional anthracycline‐based chemotherapy, keeping intensified treatment for relapsing cases, considering involved‐field radiotherapy, and CNS prophylaxis in high‐risk patients.

The clinical features, management and prognostic effects of pathological fractures in a multicenter series of 373 patients with diffuse large B-cell lymphoma of the bone

BACKGROUNDnPathological fractures (PFs) occur in 10%-20% of patients with diffuse large B-cell lymphoma (DLBCL) of the bone. The clinical features and the effects of this severe complication on management and prognosis have not been previously analyzed in a large series.nnnPATIENTS AND METHODSnThe effects of PF on management and prognosis were reviewed in an international retrospective series of 373 patients with newly diagnosed bone DLBCL, comparing 78 patients with PF at presentation (group PF-BL) and 295 patients without PF (controls).nnnRESULTSnAt a median follow-up of 53 months (range 3-246), PF-BL patients exhibited lower rates of overall response (ORR, 78% versus 85%; P = 0.17), 5-year progression-free survival (PFS, 53 ± 6% versus 61 ± 3%; P = 0.02) and 5-year overall survival (OS, 54 ± 6% versus 68 ± 3%, P = 0.008) than controls. Initial surgical stabilization of the PF did not change therapeutic outcome (5-year OS: 45 ± 9% versus 54 ± 10%; P = 0.20). PF-BL patients referred to irradiation of the fractured bone before chemotherapy exhibited a significantly poorer outcome than patients managed with the inverse sequence (ORR: 52% versus 92%, P = 0.0005; 5-year OS: 22 ± 14% versus 64 ± 9%, P = 0.007). Multivariate analysis confirmed the independent association between PF and worse survival and the negative effect of radiotherapy as initial therapy.nnnCONCLUSIONnFracture is an independent, adverse prognostic event in patients with bone DLBCL. Anthracycline-based chemotherapy followed by radiotherapy seems to be the better treatment sequence. Initial fracture stabilization does not seem to improve outcome; it should be used to improve patients quality of life only if chemotherapy delays can be avoided.