Outcomes of Patients Treated in the UK Proton Overseas Programme: Non-central Nervous System Group.

AIMS: The UK Proton Overseas Programme (POP) was launched in 2008. The Proton Clinical Outcomes Unit (PCOU) warehouses a centralised registry for collection, curation and analysis of all outcomes data for all National Health Service-funded UK patients referred and treated abroad with proton beam therapy (PBT) via the POP. Outcomes are reported and analysed here for patients diagnosed with non-central nervous system tumours treated from 2008 to September 2020 via the POP. MATERIALS AND METHODS: All non-central nervous system tumour files for treatments as of 30 September 2020 were interrogated for follow-up information, and type (following CTCAE v4) and time of onset of any late (>90 days post-PBT completion) grade 3-5 toxicities. RESULTS: Four hundred and ninety-five patients were analysed. The median follow-up was 2.1 years (0-9.3 years). The median age was 11 years (0-69 years). 70.3% of patients were paediatric (<16 years). Rhabdomyosarcoma (RMS) and Ewing sarcoma were the most common diagnoses (42.6% and 34.1%). 51.3% of treated patients were for head and neck (H&N) tumours. At last known follow-up, 86.1% of all patients were alive, with a 2-year survival rate of 88.3% and 2-year local control of 90.3%. Mortality and local control were worse for adults (≥25 years) than for the younger groups. The grade 3 toxicity rate was 12.6%, with a median onset of 2.3 years. Most were in the H&N region in paediatric patients with RMS. Cataracts (30.5%) were the most common, then musculoskeletal deformity (10.1%) and premature menopause (10.1%). Three paediatric patients (1-3 years at treatment) experienced secondary malignancy. Seven grade 4 toxicities occurred (1.6%), all in the H&N region and most in paediatric patients with RMS. Six related to eyes (cataracts, retinopathy, scleral disorder) or ears (hearing impairment). CONCLUSIONS: This study is the largest to date for RMS and Ewing sarcoma, undergoing multimodality therapy including PBT. It demonstrates good local control, survival and acceptable toxicity rates.

TROG 14.04: Multicentre Study of Feasibility and Impact on Anxiety of DIBH in Breast Cancer Patients.

AIMS: The aim of TROG 14.04 was to assess the feasibility of deep inspiration breath hold (DIBH) and its impact on radiation dose to the heart in patients with left-sided breast cancer undergoing radiotherapy. Secondary end points pertained to patient anxiety and cost of delivering a DIBH programme. MATERIALS AND METHODS: The study comprised two groups - left-sided breast cancer patients engaging DIBH and right-sided breast cancer patients using free breathing through radiotherapy. The primary end point was the feasibility of DIBH, defined as left-sided breast cancer patients' ability to breath hold for 15 s, decrease in heart dose in DIBH compared with the free breathing treatment plan and reproducibility of radiotherapy delivery using mid-lung distance (MLD) assessed on electronic portal imaging as the surrogate. The time required for treatment delivery, patient-reported outcomes and resource requirement were compared between the groups. RESULTS: Between February and November 2018, 32 left-sided and 30 right-sided breast cancer patients from six radiotherapy centres were enrolled. Two left-sided breast cancer patients did not undergo DIBH (one treated in free breathing as per investigator choice, one withdrawn). The mean heart dose was reduced from 2.8 Gy (free breathing) to 1.5 Gy (DIBH). Set-up reproducibility in the first week of treatment assessed by MLD was 1.88 ± 1.04 mm (average ± 1 standard deviation) for DIBH and 1.59 ± 0.93 mm for free breathing patients. Using a reproducibility cut-off for MLD of 2 mm (1 standard deviation) as per study protocol, DIBH was feasible for 67% of DIBH patients. Radiotherapy delivery using DIBH took about 2 min longer than for free breathing. Anxiety was not significantly different in DIBH patients and decreased over the course of treatment in both groups. CONCLUSION: Although DIBH was shown to require about 2 min longer per treatment slot, it has the potential to reduce heart dose in left-sided breast cancer patients by nearly a half, provided careful assessment of breath hold reproducibility is carried out.

A Novel Model and Infrastructure for Clinical Outcomes Data Collection and Their Systematic Evaluation for UK Patients Receiving Proton Beam Therapy.

AIMS: To establish an infrastructure for sustainable, comprehensive data collection and systematic outcomes evaluation for UK patients receiving proton beam therapy (PBT). MATERIALS AND METHODS: A Proton Outcomes Working Group was formed in 2014 to develop a national minimum dataset for PBT patients and to define a clinically integrated informatics solution for data collection. The Christie Proton Beam Therapy Centre formed its Proton Clinical Outcomes Unit in 2018 to collect, curate and analyse outcomes data prospectively for UK-treated patients and retrospectively for UK patients referred abroad for PBT since 2008 via the Proton Overseas Programme (POP). RESULTS: A single electronic form (eForm) was developed to capture the agreed data, using a data tree approach including conditional logic: data items are requested once, further questions depend on previous answers and are sensitive to tumour site and patient pathway time point. Relevant data automatically populate other forms, saving time, prompting completeness of clinical assessments and ensuring data consistency. Completed eForm data populate the electronic patient record and generate individualised outputs, including consultation letters, treatment summary and surveillance plans, based on organs at risk irradiated, age and sex. All data regarding POP-treated patients are verified and migrated into the system, ensuring that patient data, whether overseas or UK treated, are consistently recorded. The eForm utilises a 'user friendly' web portal interface, the Clinical Web Portal, including clickable tables and infographics. Data items are coded to a universally recognised standard comparable with other data systems. Patient-reported outcomes are also integrated, highlighting significant toxicities and prompting a response. Outcomes data can be correlated with dosimetric DICOM data to support radiation dose modelling. CONCLUSION: Outcomes data from both POP-treated and The Christie-treated patients support long-term care, allow evaluation of PBT efficacy and safety, assist future selection of PBT patients and support hypothesis generation for future clinical trials.

Limb preservation surgery with extracorporeal irradiation in the management of malignant bone tumor: the oncological outcomes of 101 patients.

BACKGROUND: En bloc resection, extracorporeal irradiation (ECI) and reimplantation have been used selectively at our centers as part of limb preservation surgery of malignant bone tumors since 1996. We report the long-term oncological outcomes. PATIENTS AND METHODS: One hundred one patients were treated with ECI at two Australian centers between 1996 and 2011. A single dose of 50 Gy was delivered to the resected bone segments. The irradiated bones were reimplanted immediately as a biological graft. Patients were treated with chemotherapy as per standard protocol. The three main histological diagnoses were Ewing's sarcoma (35), osteosarcoma (37) and chondrosarcoma (20). There were nine patients with a range of different histologies. RESULTS: There was one local recurrence (2.86%) in Ewing's sarcoma and the 5-year cumulative overall survival was 81.9%. There was no local recurrence in osteosarcoma and five distant recurrences. The 5-year cumulative overall survival was 85.7%. The local recurrence rate was 20% (4 of 20) in chondrosarcoma, and the 5-year cumulative overall survival was 80.8%. Limb preservation was achieved in 97 patients. For the 64 patients with disease in the pelvis or lower limb, 53 (82.3%) could walk without aids at the time of last follow-up. CONCLUSIONS: This large series of ECI shows an excellent long-term local control. It is a good alternative reconstruction method in selected patients. The overall survival is comparable to other published series.

Paediatric medulloblastoma: patterns of care and radiotherapy quality assurance in Australia.

The purpose of this study was to document how children in Australia with medulloblastoma are being treated and to evaluate the quality of radiotherapy (RT) delivered. The Radiotherapy Database of the Australian and New Zealand Children's Haematology and Oncology Group was used to identify 46 children with medulloblastoma younger than the age of 15 years treated with radical intent by craniospinal irradiation between 1997 and 1999 inclusively. Twenty-six patients had completely resected disease without evidence of disease spread. Of these, 16 patients received a craniospinal RT dose of <25 Gy in addition to chemotherapy. RT treatment immobilization methods varied, as did planning methods. RT dose to critical structures was recorded on treatment plans for only 15% of patients. The average systematic error in shield placement at the posterior orbit was 5.2 mm, and two-thirds of patients were 'overshielded' at this site. Adequate coverage of the distal end of the thecal sac was achieved in fewer than 50% of on-treatment verification films for 21 of 45 patients. With a reduction in RT dose to the craniospinal axis for paediatric medulloblastoma, greater attention is needed for patient immobilization, documentation of RT dose to critical structures and the placement and reproducibility of shielding.

Importance of radiation time and dose factors on outcome for childhood medulloblastoma.

The purpose of this study was to investigate the relationship of posterior fossa radiation therapy duration (PFRTD) and relapse-free survival (RFS) following adjuvant craniospinal RT for childhood medulloblastoma. A retrospective audit was performed assessing all children aged <18 years managed with adjuvant craniospinal RT for medulloblastoma in Australia and New Zealand in 1980-1993. Children receiving prolonged (>180 days) pre-RT chemotherapy were excluded. Data were obtained for potential prognostic factors in domains of patient, tumour and treatment factors. Radiation therapy time factors assessed were PFRTD and time interval from surgery to commencement of RT (SRTD). The end-point assessed was RFS and analysis was performed using Cox regression and Kaplan-Meier survival. One hundred and eighty-nine children were identified from 10 oncology units, with data available from 182 children for analysis. Median follow up was 5.3 years. Seventy-three per cent of children presented with disease confined to the cerebellum; 13% had initial neuraxis disease. Macroscopic resection was described in 54%; 42% received adjuvant chemotherapy. Median RT dose and RT duration to PF was 55 Gy and 45 days, respectively. Seventy-eight relapses occurred with a 10-year actuarial RFS of 58.2% (standard error +/- 4%). On univariate analysis, increasing PF dose (P = 0.002), age >5 years (P = 0.006), and more thorough extent of surgical resection (P = 0.043) were associated with improved RFS; PFRTD (P = 0.20) and SRTD (P = 0.51) were not associated with RFS. On multivariate analysis, although both PF dose (P = 0.004) and extent of surgery (P = 0.045) remained strongly significant, RT duration was now associated with RFS (P = 0.049). Other factors assessed that did not reach significance were patient age, local tumour extent, presence of internal shunt and use of chemotherapy. The importance of local treatment factors was confirmed in this audit with established prognostic factors such as primary tumour macroscopic resection and adequate PF RT dose being associated with RFS. A treatment time effect is weakly suggested, although less significant than RT dose delivered.

Absence of adverse early quality of life outcomes of radiation therapy in breast conservation therapy for early breast cancer.

The New South Wales Breast Radiation Oncology Group has completed a prospective multicentre study of the impact of radiation therapy (RT) on acute toxicity and quality of life (QoL) in women with early breast cancer treated with breast conservation therapy. The patient group received adjuvant breast tangential RT after wide local excision of breast cancer. Acute toxicity and cosmesis was assessed quantitatively and qualitatively. European Organization of Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-30) and Perceived Adjustment to Chronic Illness Scale (PACIS) were the QoL instruments used. Of 175 women, 34.3% described lethargy leading to a significant disruption to normal activity during RT. At week 6, this had reduced to 7.5% reporting significant lethargy. No negative effects on QoL were noted over the time period of RT; EORTC demonstrated no difference (P = 0.79). PACIS recorded a significant improvement in functioning (P < 0.001) from baseline to week 6. Univariate analysis on potential predictive patient, tumour and treatment factors demonstrated an association of baseline pre-RT breast discomfort with worse lethargy (P = 0.03), EORTC (P < 0.01) and PACIS (P < 0.01) measures. This study confirms the minimal impact of RT on patient functioning at 6 weeks post-treatment.

Why a breast boost should remain a controversial aspect of routine breast conservation management in Australia and New Zealand in 2002.

Two randomized trials have recently shown a statistically significant improvement in local control when a boost is employed in the conservative treatment of early breast cancer. However, unresolved issues of cost effectiveness, potentially increased toxicity and the inability to automatically generalize these results to Australian and New Zealand practice remain. In view of these unresolved controversies, the St George and Wollongong hospitals breast boost trial (SGW trial) will continue to recruit.

Extracorporeal irradiation for malignant bone tumors.

PURPOSE: Extracorporeal irradiation (ECI) has been used selectively in the management of primary malignant bone tumors since 1996. We report our techniques for ECI and the short-term oncologic and orthopedic outcomes. METHODS AND MATERIALS: Sixteen patients with primary malignant bone tumors were treated with ECI from 1996 to 2000. The median age was 14 years. The histologic diagnoses were Ewing's sarcoma (11), osteosarcoma (4) and chondrosarcoma (1). The treated sites were femur (7), tibia (4), humerus (2), ilium (2), and sacrum (1). Following induction chemotherapy in Ewing's sarcomas and osteosarcoma, en bloc resection of the tumor and tumor-bearing bone was performed. A single dose of 50 Gy was delivered to the bone extracorporeally using either a linear accelerator (9 cases) or a blood product irradiator (7 cases). The orthopedic outcome was recorded using a standard functional scale. RESULTS: At a median follow-up of 19.5 months, there were no cases of local recurrence or graft failure. One patient required amputation due to chronic osteomyelitis. For the 10 patients with follow-up greater than 18 months, the functional outcomes were graded good to excellent. CONCLUSION: The short-term oncologic and orthopedic results are encouraging and suggest that ECI provides a good alternative for reconstruction in limb conservative surgery in selected patients. This technique should only be used in a multidisciplinary setting, where careful follow-up is available to assess the long-term outcomes.

Three-dimensional dose distribution of tangential breast irradiation: results of a multicentre phantom dosimetry study.

BACKGROUND AND PURPOSE: One aspect of good radiotherapeutic practice is to achieve dose homogeneity. Dose inhomogeneities occur with breast tangent irradiation, particularly in women with large breasts. MATERIALS AND METHODS: Ten Australian radiation oncology centres agreed to participate in this multicentre phantom dosimetry study. An Alderson radiation therapy anthropomorphic phantom with attachable breasts of two different cup sizes (B and DD) was used. The entire phantom was capable of having thermoluminescent dosimeters (TLD) material inserted at various locations. Nine TLD positions were distributed throughout the left breast phantom including the superior and inferior planes. The ten centres were asked to simulate, plan and treat (with a prescription of 100 cGy) the breast phantoms according to their standard practice. Point doses from resultant computer plans were calculated for each TLD position. Measured and calculated (planning computer) doses were compared. RESULTS: The dose planning predictability between departments did not appear to be significantly different for both the small and large breast phantoms. The median dose deviation (calculated dose minus measured dose) for all centres ranged from 2. 3 to 5.3 cGy on the central axis and from 2.1 to 7.5 cGy for the off-axis planes. The highest absolute dose was measured in the inferior plane of the large breast (128.7 cGy). The greatest dose inhomogeneity occurred in the small breast phantom volume (median range 93.2-105 cGy) compared with the large breast phantom volume (median range, 100.1-107.7 cGy). There was considerable variation in the use (or not) of wedges to obtain optimized dosimetry. No department used 3D compensators. CONCLUSION: The results highlight areas of potential improvement in the delivery of breast tangent radiotherapy. Despite reasonable dose predictability, the greatest dose deviation and highest measured doses occurred in the inferior aspects of both the small and large breast phantoms.

Local recurrence after mastectomy and adjuvant CMF: implications for adjuvant radiation therapy.

BACKGROUND: The purpose of the present study was to evaluate the patterns of failure in a series of patients with node-positive breast cancer that was treated by total mastectomy and adjuvant chemotherapy. METHODS: A retrospective review was undertaken of 217 patients with node-positive breast cancer who were referred to the oncology departments of Westmead and Nepean Hospitals following total mastectomy between January 1980 and December 1991. The majority of patients (82%) were pre- or peri-menopausal and all underwent chemotherapy with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) by either an oral or intravenous regimen. No patient received adjuvant radiation therapy. RESULTS: After a median follow up of 8.7 years, 19% of patients had developed a loco-regional recurrence (LRR). The majority of LRR (79%) occurred within the initial 3 years after mastectomy. The risk of LRR was positively associated with the size of the tumour (11% for T1 vs 53% for T3, P < 0.001) and axillary nodal status (16% for three or fewer positive nodes vs 31% for four or more positive nodes, P = 0.017). Patients with T1 or T2 tumours and 1-3 positive nodes had the lowest rate of LRR (11%) while those with T3 tumours or 4-10 positive nodes had the highest rates, ranging from 23 to 75%. Relapse at the chest wall and supraclavicular fossa (SCF) accounted for 46 and 35%, respectively, of all LRR; relapse at the internal mammary chain and axilla was uncommon. CONCLUSION: The data suggest that patients with T3 tumours (> 5 cm) and any nodal involvement or patients with four or more involved axillary nodes, regardless of T stage, are at a high risk of LRR and will benefit from adjuvant radiation therapy to the chest wall and SCF.

Splenosis mimicking metastases from breast carcinoma.

The case history is presented of a patient with breast cancer who was extensively investigated for presumed hepatic metastases, which were finally diagnosed as splenosis, the heterotopic autotransplantation of splenic tissue after traumatic rupture of the spleen. This case history highlights the importance of obtaining a pathological diagnosis prior to labelling a patient as having metastatic disease. This is especially important for patients who have an unusual pattern or appearance of metastases or for whom the risk of metastatic disease is presumed to be minimal.

Radiation-induced localized scleroderma in breast cancer patients.

Radiation-induced scleroderma in breast cancer patients appears to occur in approximately one out of every 500 patients. We report four cases that developed within 3 months of conservative breast surgery and postoperative radiation treatment. The reaction was contained entirely within the treatment field and demonstrated the typical features of this condition where the breast becomes erythematous, violaceous, indurated, retracted, and progressively pigmented. The breast tends to soften and become more comfortable over 1-4 years; however, significant induration, retraction and pigmentary changes remain. There appears to be no predictive factors. Radiation-induced scleroderma must be differentiated from cellulitis and recurrent breast cancer.

Management of high-risk node-positive breast cancer by standard-dose chemotherapy and loco-regional radiotherapy.

One-hundred, thirty-six women, aged up to 76 years, with high-risk breast cancer were treated with postoperative radiotherapy and 9 cycles of adjuvant chemotherapy in standard doses. Treatment-related toxicity was mild. At a median follow-up of 7.3 years, 39.6% are disease-free. At 5 and 10 years overall survival was 55% and 34% respectively; disease-free survival was 39% and 33% respectively. Eighteen patients (13.2%) developed loco-regional recurrence, which was uncontrolled in four. When compared to series treated with adjuvant chemotherapy, but without radiotherapy, there are apparent survival gains of 10-15% at 5 and 10 years. These results in both pre- and post-menopausal patients compare favourably with results of high-dose chemotherapy and stem-cell rescue in much more highly selected patients.

Locally advanced breast cancer: defining an optimum treatment regimen.

PURPOSE: This retrospective review examines response, local control and freedom from distant failure for patients with locally advanced breast cancer treated by chemotherapy and radiotherapy without routine surgery. METHODS AND MATERIALS: 67 patients were treated between January 1980 and December 1988 at Westmead Hospital, NSW, Australia. Median follow-up for surviving patients was 56 months. Four successive protocols evolved, each with three phases induction chemotherapy (adriamycin or novantrone, cyclophosphamide) (three cycles), radiotherapy then chemotherapy (cyclophosphamide, methotrexate, 5-fluorouracil) of progressively shorter duration. Radiotherapy and chemotherapy were concurrent in the fourth regimen. RESULTS: Clinical complete response (disappearance of all known disease) after chemotherapy, radiotherapy and additional chemotherapy was 18%, 55% and 79% respectively. Seven additional patients subsequently underwent mastectomy (N = 2), local excision (N = 1) or a radiation boost (N = 4) for a total complete response rate of 90%. Twenty one patients (31%) failed to achieve a complete response (N = 7) or recurred locally (N = 14). The crude 2-year rate of local recurrence was 50% for tumors > 10 cm (N = 10) and 14% for smaller tumors (n = 57) and was not influenced by protocol. Two-year actuarial freedom from distant failure was 67% at 2 years. CONCLUSION: Local control can be achieved for patients with locally advanced breast cancer with a primary tumor < 10 cm using chemotherapy and radiotherapy without routine mastectomy.

Nasopharyngeal carcinoma in the young.

This study was carried out to determine whether locoregional control of nasopharyngeal carcinoma in the young by irradiation has improved since 1975. Fifty-seven consecutive, previously untreated, patients, less than 30 years old, were diagnosed and treated at University of Toronto Hospitals between 1958 and 1990; 21 patients were treated before and 36 after 1975. Staging was as follows: M0, n = 54; M1, n = 3; T1 + T2, n = 26; T3 + T4, n = 31; N0, n = 10; N1 + N2a, n = 10; N2b + N2c, n = 24; N3, n = 13. All patients were irradiated. The primary tumour dose was 3500-7000 cGy (median 5450). Adjuvant chemotherapy was introduced in 1977. Subsequently, 10/26 (38%) M0 patients received this treatment. For all 57 patients, 10-year survival was 56%. For 52 M0 patients with complete follow-up data, 10-year survival was 63%; 10-year relapse free survival (RFS) was 61%. Age, sex, race, and histology were not significant variables. Ten-year RFS results were: T1 + T2, M0 (n = 24) 70%, T3 + T4, M0 (n = 27) 52%, (P = 0.25); N0-N2c (n = 41) 64%, N3 (n = 11) 54% (P = 0.31). Relapse occurred in 20/52 (38%) patients. Survival from the date of first relapse was 10% at 10 years. No patient with systemic relapse survived. Only 1/32 (3%) patients treated after 1975 developed an isolated locoregional relapse, giving a 10-year isolated locoregional relapse free rate (LR RFS) of 96%, compared with 5/20 (25%) prior to 1975, which gave a 10-year LR RFS of 75% (P = 0.05). Two of the five patients who relapsed before 1975 were salvaged by re-irradiation. Systemic relapse, either alone or combined with locoregional relapse, accounted for 6/11 (55%) relapses before 1975 and 8/9 (89%) after 1975. Ten-year systemic RFS was 90% for patients who received adjuvant chemotherapy (n = 10) and 72% for patients treated since 1977 by irradiation alone (n = 16) (P = 0.41). Isolated local relapse was exceptional in patients treated after 1975 (1/32).(ABSTRACT TRUNCATED AT 250 WORDS)

Hypercalcaemia in small cell lung cancer: report of a case associated with parathyroid hormone-related protein (PTHrP).

Although hypercalcaemia is frequently associated with malignancy, it is very rare in small cell lung cancer despite the high incidence of lytic bone metastases. We report a patient with extensive small cell cancer who presented with hypercalcaemia. Investigations suggested parathyroid hormone (PTH) receptor stimulation, although the serum PTH level was not elevated. PTH related protein (PTHrP) was localised in a biopsy specimen from the tumour. Although hypercalcaemia is rare in small cell lung cancer, when hypercalcaemia does occur, PTHrP may be a causal factor.

Paraneoplastic myelopathy at diagnosis in a patient with pathologic stage 1A Hodgkin disease.

The case of a patient with pathologic Stage 1A Hodgkin disease is reported in whom subacute paraneoplastic myelopathy developed before treatment. Myelography, computed tomography, magnetic resonance imaging, and lumbar puncture examination showed no evidence of central nervous system involvement. The patient was treated with combination chemotherapy (to avoid spinal cord exposure to radiation) without neurologic improvement. The patient's neurologic condition responded well to intrathecal dexamethasone.