Ovarian function after chemotherapy in young breast cancer survivors.

BACKGROUND: As cure rates for breast cancer improve, there is increasing evidence that late effects of treatment-and impaired fertility in particular-are emerging as important concerns among young breast cancer survivors. Older reports have evaluated the occurrence of amenorrhea after treatment, but few data have been reported about the incidence of biochemical evidence for impaired ovarian function in patients who do not become overtly menopausal. METHODS: We conducted a cross-sectional study evaluating anti-Müllerian hormone (amh) in premenopausal chemotherapy-treated breast cancer survivors and control patients. Random serum levels of amh and other relevant clinical data were collected for 100 premenopausal chemotherapy-treated breast cancer survivors and 76 control subjects. Subgroup analyses were performed for women with regular menstrual cycles at the time of amh testing. RESULTS: After adjustment for age, amh was significantly lower in the overall group of patients receiving chemotherapy (p = 0.002) and in the subgroup reporting normal cycles (p = 0.03). Cyclophosphamide produced a significant dose-dependent reduction in amh (p < 0.001); trastuzumab was associated with increased amh in survivors with normal cycles. Overall, serum amh in survivors was roughly equivalent to that measured in control patients 12 years older. CONCLUSIONS: Young breast cancer survivors often experience significant impairment of ovarian function despite having normal menstrual cycles after treatment. Those results have important implications for patient counselling and the timing of possible referral to a fertility specialist.

Pancreatic cancer risk after treatment of Hodgkin lymphoma.

BACKGROUND: Although elevated risks of pancreatic cancer have been observed in long-term survivors of Hodgkin lymphoma (HL), no prior study has assessed the risk of second pancreatic cancer in relation to radiation dose and specific chemotherapeutic agents. PATIENTS AND METHODS: We conducted an international case-control study within a cohort of 19 882 HL survivors diagnosed from 1953 to 2003 including 36 cases and 70 matched controls. RESULTS: Median ages at HL and pancreatic cancer diagnoses were 47 and 60.5 years, respectively; median time to pancreatic cancer was 19 years. Pancreatic cancer risk increased with increasing radiation dose to the pancreatic tumor location (Ptrend = 0.005) and increasing number of alkylating agent (AA)-containing cycles of chemotherapy (Ptrend = 0.008). The odds ratio (OR) for patients treated with both subdiaphragmatic radiation (≥10 Gy) and ≥6 AA-containing chemotherapy cycles (13 cases, 6 controls) compared with patients with neither treatment was 17.9 (95% confidence interval 3.5-158). The joint effect of these two treatments was significantly greater than additive (P = 0.041) and nonsignificantly greater than multiplicative (P = 0.29). Especially high risks were observed among patients receiving ≥8400 mg/m(2) of procarbazine with nitrogen mustard or ≥3900 mg/m(2) of cyclophosphamide. CONCLUSION: Our study demonstrates for the first time that both radiotherapy and chemotherapy substantially increase pancreatic cancer risks among HL survivors treated in the past. These findings extend the range of nonhematologic cancers associated with chemotherapy and add to the evidence that the combination of radiotherapy and chemotherapy can lead to especially large risks.

Surrogate-free machine learning-based organ dose reconstruction for pediatric abdominal radiotherapy.

To study radiotherapy-related adverse effects, detailed dose information (3D distribution) is needed for accurate dose-effect modeling. For childhood cancer survivors who underwent radiotherapy in the pre-CT era, only 2D radiographs were acquired, thus 3D dose distributions must be reconstructed from limited information. State-of-the-art methods achieve this by using 3D surrogate anatomies. These can however lack personalization and lead to coarse reconstructions. We present and validate a surrogate-free dose reconstruction method based on Machine Learning (ML). Abdominal planning CTs (n = 142) of recently-treated childhood cancer patients were gathered, their organs at risk were segmented, and 300 artificial Wilms' tumor plans were sampled automatically. Each artificial plan was automatically emulated on the 142 CTs, resulting in 42,600 3D dose distributions from which dose-volume metrics were derived. Anatomical features were extracted from digitally reconstructed radiographs simulated from the CTs to resemble historical radiographs. Further, patient and radiotherapy plan features typically available from historical treatment records were collected. An evolutionary ML algorithm was then used to link features to dose-volume metrics. Besides 5-fold cross validation, a further evaluation was done on an independent dataset of five CTs each associated with two clinical plans. Cross-validation resulted in mean absolute errors ≤ 0.6 Gy for organs completely inside or outside the field. For organs positioned at the edge of the field, mean absolute errors ≤ 1.7 Gy for [Formula: see text], ≤ 2.9 Gy for [Formula: see text], and ≤ 13% for [Formula: see text] and [Formula: see text], were obtained, without systematic bias. Similar results were found for the independent dataset. To conclude, we proposed a novel organ dose reconstruction method that uses ML models to predict dose-volume metric values given patient and plan features. Our approach is not only accurate, but also efficient, as the setup of a surrogate is no longer needed.

Screening mammography for young women treated with supradiaphragmatic radiation for Hodgkin's lymphoma.

BACKGROUND: Female survivors of Hodgkin's lymphoma (HL) treated with supradiaphragmatic radiation therapy (SRT) are at increased risk of breast cancer (BC), but there is little data on the optimal screening strategy. PATIENT AND METHODS: We report a prospective surveillance study of women treated for HL with SRT before age 30 participating in a high-risk screening clinic. Starting 8 years after treatment, women received annual mammography and clinical follow-up from 1997 to 2006. Method of detection and characteristics of BCs were identified. RESULTS: In all, 115 female HL survivors attended at least one clinic; 100 participated in annual surveillance. The majority had mammography alone; adjunctive magnetic resonance imaging (MRI) was used more frequently in women with high breast density (P = 0.025). Median age at first mammogram was 36 years and decreased with more recent year of diagnosis. Twelve of the 100 participating women (12%) were diagnosed with BC after a median of 5 years of surveillance (range, 1-9). Seven BCs presented as palpable masses [six invasive, one ductal carcinoma in situ (DCIS)], five were detected by mammography (one invasive, four DCIS). CONCLUSIONS: Despite earlier initiation of mammographic screening, most BCs were detected clinically and had unfavorable pathologic characteristics. Evaluation of more intensive screening and the contribution of MRI for earlier detection is warranted.

Best Practice Recommendations for the Retention of Radiotherapy Records.

This paper offers best practice recommendations for the maintenance and retention of radiotherapy health records and technical information for cancer programmes. The recommendations are based on a review of the published and grey literature, feedback from key informants from seven countries and expert consensus. Ideally, complete health records should be retained for 5 years beyond the patient's lifetime, regardless of where they are created and maintained. Technical information constituting the radiotherapy plan should also be retained beyond the patient's lifetime for 5 years, including the primary images, contours of delineated targets and critical organs, dose distributions and other radiotherapy plan objects. There have been increased data storage and access requirements to support modern image-guided radiotherapy. Therefore, the proposed recommendations represent an ideal state of radiotherapy record retention to facilitate ongoing safe and effective care for patients as well as meaningful and informed retrospective research and policy development.

Impact of patient and provider characteristics on the treatment and outcomes of colorectal cancer.

While the management and prognosis of colorectal cancer are largely dependent on clinical features such as tumor stage, there is considerable variation in treatment and outcome not explained by traditional prognostic factors. To guide efforts by researchers and health-care providers to improve quality of care, we review studies of variation in treatment and outcome by patient and provider characteristics. Surgeon expertise and case volume are associated with improved tumor control, although surgeon and hospital factors are not associated consistently with perioperative mortality or long-term survival. Some studies indicate that patients are less likely to undergo permanent colostomy if they are treated by high-volume surgeons and hospitals. Differences in treatment and outcome of patients managed by health maintenance organizations or fee-for-service providers have not generally been found. Older patients are less likely to receive adjuvant therapy after surgery, even after adjustment for comorbid illness. In the United States, black patients with colorectal cancer receive less aggressive therapy and are more likely to die of this disease than white patients, but cancer-specific survival differences are reduced or eliminated when black patients receive comparable treatment. Patients of low socioeconomic status (SES) have worse survival than those of higher SES, although the reasons for this discrepancy are not well understood. Variations in treatment may arise from inadequate physician knowledge of practice guidelines, treatment decisions based on unmeasured clinical factors, or patient preferences. To improve quality of care for colorectal cancer, a better understanding of mechanisms underlying associations between patient and provider characteristics and outcomes is required.

Solitary plasmacytoma treated with radiotherapy: impact of tumor size on outcome.

PURPOSE: Solitary plasmacytoma (SP) is a rare presentation of plasma cell neoplasms. In contrast to multiple myeloma, long-term disease-free survival and cure is possible following local radiotherapy (RT), particularly for soft tissue presentations. In this study, we attempt to identify factors that predict for local failure, progression to multiple myeloma, and disease-free survival (DFS) in patients mainly managed with local RT. METHODS AND MATERIALS: We identified 46 patients referred to the Princess Margaret Hospital between 1982 and 1993. The median age was 63 years (range 35-95), with a male:female ratio of 1.9:1. All patients had biopsy-proven SP (osseous: 32, soft tissue: 14). M-protein was abnormal in 19 patients (41%). All patients were treated with local RT (median dose 35 Gy), with 5 patients (11%) also receiving chemotherapy. Maximum tumor size pre-RT ranged from 0 to 18 cm (median 2.5). RESULTS: The 8-year overall survival, DFS, and myeloma-free rates were 65%, 44%, and 50%, respectively. The local control rate was 83%. Factors predictive of progression to myeloma (and poorer DFS) included bone presentation and older age. However, these two factors did not influence local control, which was affected by tumor size. All tumors < 5 cm in bulk (34 patients) were controlled by RT. Anatomic location did not predict outcome; however, 3 of the 5 tumors arising in paranasal sinuses did not achieve local control. Lower RT dose (< or =35 Gy) was not associated with a higher risk of local failure. CONCLUSION: Solitary plasmacytomas are effectively treated with moderate-dose RT, although osseous tumors have a high rate of recurrence as systemic myeloma. Large tumor bulk locally (> or =5 cm) predicts for local failure. Combined chemotherapy and RT should be investigated in these high-risk patients to increase the local control rate and the cure rate.

The impact of irregularly rising prostate-specific antigen and "impending failure" on the apparent outcome of localized prostate cancer following radiotherapy.

PURPOSE: To examine the impact of irregularly rising prostate-specific antigen (PSA) and "impending" biochemical failure on the apparent rate of biochemical relapse following radiotherapy for localized prostate cancer. METHODS AND MATERIALS: We analyzed the outcome of 572 patients with T1/T2 prostate cancer treated with radiotherapy alone at the Princess Margaret Hospital (median follow-up, 4.21 years). Biochemical outcomes were analyzed using 2 different definitions of failure: (1) the American Society for Therapeutic Radiology and Oncology (ASTRO) definition, and (2) a modified definition that included 2 consecutive rises in PSA, with a minimum rise of 1.5 ng/mL above the nadir, or a nadir value of greater than 4 ng/mL. Patients were defined as having "impending failure" when the last 2 PSA measurements taken demonstrated 2 consecutive rises. RESULTS: Two-hundred and thirty patients (40%) met the ASTRO definition of failure; 258 patients (48%) failed by the modified definition (p = 0.001). Five-year biochemical relapse-free rate (bNED) rate was 55% using the ASTRO definition, and 49% using the modified definition. This difference in 5-year bNED was greatest for patients with high-risk disease (ASTRO definition 30% vs. modified definition 15%). Twenty-four of the 38 additional cases identified as biochemical failures by the modified definition had irregularly rising PSA levels; 14 were "impending failures." These additional 38 patients had a median PSA elevation 5.4 ng/mL above the nadir, and a high risk of subsequent clinical failure (4-year clinical failure-free rate of 63%). The ASTRO definition had a sensitivity of 87% and specificity of 74% for predicting clinical relapse. The modified definition had a sensitivity of 95% and a specificity of 70%. CONCLUSION: A definition of biochemical failure that includes an absolute allowable rise in PSA above the nadir can identify patients with rising PSA who are at substantial risk of clinical relapse, but who are not defined as biochemical failures by the ASTRO definition. This is particularly true for patients with high-risk disease. The use of a uniform definition of biochemical failure is crucial to ensure that differences in apparent outcome are not due to differences in the definition of relapse. Currently, the ASTRO definition should remain the standard. Large cohort studies with long follow-up can be utilized to optimize the definition of biochemical failure following radiotherapy for prostate cancer.

Stage I and II MALT lymphoma: results of treatment with radiotherapy.

PURPOSE: Mucosa-associated lymphoid tissue (MALT) lymphoma is a distinct disease with specific clinical and pathologic features that may affect diverse organs. We analyzed our recent experience with Stage I/II MALT lymphoma presenting in the stomach and other organs to assess the outcome following involved field radiation therapy (RT). PATIENTS AND METHODS: Seventy patients with Stage IE (62) and IIE (8) disease were treated between 1989 and 1998. Patients with transformed MALT were excluded. The median age was 62 years (range, 24--83 years), M:F ratio 1:2.2. Presenting sites included stomach, 15; orbital adnexa, 19; salivary glands, 15; thyroid, 8; lung, 5; upper airways, 3 (nasopharynx, 2; larynx, 1); urinary bladder, 3; breast, 1; and rectum, 1. Staging included site-specific imaging, CT abdomen in 66 patients (94%) and bone marrow biopsy in 54 (77%). Sixty-two patients received radiation therapy: 52 received RT alone, 7 received chemotherapy and RT, and 3 received antibiotics followed by RT. Median RT dose was 30 Gy (range, 17.5--35 Gy). Most frequently used RT prescriptions were 25 Gy (26 patients-18 orbit, 6 stomach, and 2 salivary glands), 30 Gy (23 patients), and 35 Gy (8 patients). Five patients had complete surgical excision of lymphoma and no other treatment (stomach 1, salivary 2, lung 2), whereas 2 patients with gastric lymphoma received antibiotics only. One patient refused treatment and was excluded from the analysis of treatment outcome, leaving 69 patients with a median follow-up of 4.2 years (range, 0.3-11.4 years). RESULTS: A complete response was achieved in 66/69 patients, and 3 patients had partial response (2 lung, 1 orbit). The 5-year disease-free survival (DFS) was 76%, and the overall survival was 96%. No relapses were observed in patients with stomach and thyroid lymphoma. The 5-year DFS for these patients was 93%, in contrast to 69% for patients presenting in other sites (p = 0.006). Among the 5 patients treated with surgery only, 2 relapsed locally (lung, and minor salivary gland). Among 62 patients who received RT, 8 relapsed (2 salivary, 3 orbit, 1 nasopharynx, 1 larynx, 1 breast). Three patients relapsed in the nonirradiated contralateral paired organ, 4 in distant sites, and 1 in both local and distant sites. The overall local control rate with radiation was 97% (60/62 patients). CONCLUSION: Localized MALT lymphomas have excellent prognosis following moderate-dose RT. Gastric and thyroid MALT lymphomas have better early outcome, as compared to the other sites where distant failure is more common. Relapses were observed in nonirradiated paired organs or distant sites. Further follow-up is required to assess the impact of failure on survival.

Radiosurgery in the management of pediatric brain tumors.

OBJECTIVE: To describe the outcome of pediatric brain tumor patients following stereotactic radiosurgery (SRS), and factors associated with progression-free survival. METHODS: We reviewed the outcome of 90 children treated with SRS for recurrent (n = 62) or residual (n = 28) brain tumors over a 10-year period. Median follow-up from SRS was 24 months for all patients and 55.5 months for the 34 patients currently alive. RESULTS: The median progression-free survival (PFS) for all patients was 13 months. Median PFS according to tumor histology was medulloblastoma = 11 months, ependymoma = 8.5 months, glioblastoma and anaplastic astrocytoma = 12 months. Median PFS in patients treated to a single lesion was 15.4 months. No patient undergoing SRS to more than 1 lesion survived disease free beyond 2 years. After adjusting for histology and other clinical factors, SRS for tumor recurrence (RR = 2.49) and the presence of > 1 lesion (RR = 2.3) were associated with a significantly increased rate of progression (p < 0.05). Three-year actuarial local control (LC) was as follows: medulloblastoma = 57%, ependymoma = 29%, anaplastic astrocytoma/glioblastoma = 60%, other histologies = 56%. Nineteen patients with radionecrosis and progressive neurologic symptoms underwent reoperation after an interval of 0.6-62 months following SRS. Pathology revealed necrosis with no evidence of tumor in 9 of these cases. CONCLUSION: SRS can be given safely to selected children with brain tumors. SRS appears to reduce the proportion of first failures occurring locally and is associated with better outcome when given as a part of initial management. Some patients with unresectable relapsed disease can be salvaged with SRS. SRS to multiple lesions does not appear to be curative. Serious neurologic symptoms requiring reoperation is infrequently caused by radionecrosis alone.

Prescribing 131Iodine based on neck uptake produces effective thyroid ablation and reduced hospital stay.

PURPOSE: The aim of this study was to determine if thyroid cancer patients with low percentage neck uptake of iodine on postoperative thyroid scans can be treated with lower doses of 131Iodine while maintaining a high ablation rate. MATERIALS AND METHODS: We reviewed the records of 58 patients with differentiated thyroid cancer treated with 131I at the Princess Margaret Hospital. The activity of 131I was prescribed based on the 48 h percentage neck uptake in postoperative thyroid scans. Patients with < or =2% uptake received 1.07 GBq, patients with 2.1-4% uptake received 1.85 GBq, patients with 4.1-6% uptake received 2.80 GBq, patients with 6.1-8% uptake received 3.70 GBq and patients with >8% uptake received 4.60 GBq. When the scan suggested cervical lymph node metastases or residual tumor, 7.40 GBq was prescribed. Follow-up scans were performed at least 5 months after 131I therapy. Successful ablation was defined as the absence of visible uptake in the neck above background. RESULTS: Forty-nine patients were included in this analysis. The ablation rate according to the prescribed activity was as follows: 1.07 GBq, 16/20 (80%); 1.85 GBq, 4/5 (80%); 2.80 GBq, 1/1 (100%); 3.70 GBq, 0/1 (0%); 4.60 GBq, 7/8 (88%); 7.40 GBq, 13/14 (93%). The ablation rate for all patients treated on the protocol was 41/49 (84%, 95% CI 70-93%). For the group treated for remnant ablation, the overall ablation rate was 28/35 (80%, 95% CI 63-92%). Twenty-two (38%) of the 58 eligible patients received 1.07 GBq as outpatients. This saved 38 hospitalization days compared to a policy of treating all patients requiring remnant ablation with 3.70 GBq. CONCLUSIONS: We conclude that patients with less iodine uptake in postoperative thyroid scans can receive lower activities of 131I, allowing a significant proportion of patients to be treated on an outpatient basis while maintaining a high ablation rate.

Evolution of treatment for Hodgkin's disease: a population-based study of radiation therapy use and outcome.

AIM: To examine changes in radiotherapy (RT) use, cause-specific survival (CSS), and overall survival (OS) in a population-based cohort of Hodgkin's disease (HD) patients diagnosed from 1982 to 1996. MATERIALS AND METHODS: Adult patients with HD diagnosed from 1 January 1982 to 31 December 1996 (n = 3957) were identified from the Ontario Cancer Registry. The cohort was divided into three consecutive 5-year periods: 1982-1986, 1987-1991, and 1992-1996. RT use, CSS and OS in each of these three periods were compared. For the entire cohort, the cumulative incidence of different causes of death was calculated. RESULTS: The proportion of patients receiving RT within 11 weeks of diagnosis declined over the three consecutive periods (25.1%, 15.6%, 11.7%, P < 0.001), as did the proportion receiving RT within 45 weeks (57.0%, 51.0%, 48.1%; P < 0.001). There was a significant increase in 5-year CSS over time (81%, 87%, 89%; P < 0.001), and OS (72%, 77%, 82%; P < 0.001), which remained significant in multivariable analyses. The cumulative incidence of death from causes other than HD was equal to the incidence of HD-related death within 12 years of diagnosis. CONCLUSIONS: There was a significant decline in the use of RT as the primary treatment modality and as part of the initial management of HD from 1982-1996 in Ontario. A greater proportion of patients received their RT after a delay consistent with the receipt of prior chemotherapy. There was also a significant increase in the CSS and OS over this period. These findings are in keeping with the adoption of effective chemotherapy in the treatment of HD.

Therapy of non-Hodgkin's lymphoma.

Non-Hodgkin's lymphomas are a heterogeneous group of malignancies of the lymphoid system. The exact etiology for most lymphomas has not been determined, but both viral and bacterial infections have been shown to be important etiologic factors. The WHO classification of hematopoietic and lymphoid tumours classifies lymphomas into B-cell and T-cell neoplasms. B-cell lymphomas account for more than 85% of all lymphomas. The Ann Arbor staging classification has been adopted by the AJCC and UICC as a standard for classifying extent of anatomic disease. The two most common histologic disease entities are follicular lymphomas and diffuse large B-cell lymphomas. The management of follicular lymphomas is used as a paradigm for the management of all indolent lymphomas. Radiation therapy is used for stage I and II disease, while alkylating agent chemotherapy, immunotherapy and radioimmunotherapy are most frequently used in stage III and IV disease that requires treatment. Most patients with follicular lymphoma enjoy prolonged survival, but at present there is no evidence that those with stage III and IV follicular lymphoma can be cured. Diffuse large B-cell lymphomas serve as a paradigm for treating aggressive lymphomas. Stage I and II diffuse large cell lymphomas are generally treated with combined modality therapy with doxorubicin-based chemotherapy followed by involved field radiation therapy, while those with stage III and IV disease are treated with chemotherapy alone. Patients who fail initial management are treated with further chemotherapy. High-dose chemotherapy with stem cell rescue has been shown to be particularly effective as salvage treatment for diffuse large cell lymphomas. The management of a heterogeneous group of primary extranodal lymphomas in general follows the above treatment principles, with additional treatment being required for those with a high risk of CNS failures, or involvement of contralateral paired organs. The management of MALT lymphomas, especially gastric MALT lymphoma, deserves special attention because of the high response rate to Helicobacter pylori eradication therapy.