Model-Based Selection for Proton Therapy in Breast Cancer: Development of the National Indication Protocol for Proton Therapy and First Clinical Experiences.

AIMS: Proton therapy is a radiation technique that yields less dose in normal tissues than photon therapy. In the Netherlands, proton therapy is reimbursed if the reduced dose to normal tissues is predicted to translate into a prespecified reduction in toxicity, based on nationally approved validated models. The aim of this paper is to present the development of a national indication protocol for proton therapy (NIPP) for model-based selection of breast cancer patients and to report on first clinical experiences. MATERIALS AND METHODS: A national proton therapy working group for breast cancer (PWG-BC) screened the literature for prognostic models able to estimate the individual risk of specific radiation-induced side-effects. After critical appraisal and selection of suitable models, a NIPP for breast cancer was written and subjected to comments by all stakeholders. The approved NIPP was subsequently introduced to select breast cancer patients who would benefit most from proton therapy. RESULTS: The model of Darby et al. (N Engl J Med 2013; 368:987-82) was the only model fulfilling the criteria prespecified by the PWG-BC. The model estimates the relative risk of an acute coronary event (ACE) based on the mean heart dose. The absolute lifetime risk of ACE <80 years was calculated by applying this model to the Dutch absolute incidence of ACE for female and male patients, between 40 and 70 years at breast cancer radiotherapy, with/without cardiovascular risk factors. The NIPP was approved for reimbursement in January 2019. Based on a threshold value of a 2% absolute lower risk on ACE for proton therapy compared with photons, 268 breast cancer patients have been treated in the Netherlands with proton therapy between February 2019 and January 2021. CONCLUSION: The NIPP includes a model that allows the estimation of the absolute risk on ACE <80 years based on mean heart dose. In the first 2 years, 268 breast cancer patients have been treated with proton therapy in The Netherlands.

Effect of breathing motion on robustness of proton therapy plans for left-sided breast cancer patients with indication for locoregional irradiation.

PURPOSE: To investigate the dosimetric impact of breathing motion on robustly optimized proton therapy treatment plans for left-sided breast cancer patients with an indication for locoregional irradiation. MATERIALS AND METHODS: Clinical Target Volumes (CTVs) (left-sided breast, level 1 to 4 axillary lymph nodes, interpectoral and internal mammary lymph node regions) and organs at risk were delineated on 4 D-CTs of ten female patients. After treatment planning to a prescribed dose of 40.05 Gy(RBE) in 15 fractions on the time-averaged CT, the dose was calculated on all ten phases of the breathing cycle. Robustness to setup (5 mm) and range errors (3%) was evaluated for those ten phases. Correlations were evaluated between the phases of the breathing cycle and the D98% of the CTV and the Dmean of the heart. RESULTS: Correlations coefficients were between -0.12 and 0.29. At the most extreme values of the 28 robustness scenarios, the clinical goals were met for all but two patients. The mean heart dose was 0.41 Gy(RBE) with a standard deviation of 0.31 Gy(RBE) of proton therapy plans. CONCLUSION: The effect of breathing motion on the robustness of proton therapy treatment plans for this patient group is minor and not of clinical significance. Based on this patient group, a deep-inspiration breath hold seems to be unnecessary to improve robustness for these patients.

Outcome of surgery for colorectal cancer in the presence of peritoneal carcinomatosis.

AIM: The detection of peritoneal carcinomatosis (PC) in colorectal cancer patients frequently results in a dilemma with regard to the optimal treatment strategy, especially when PC is encountered unexpectedly during surgery. The aim of this study was to evaluate outcomes of patients undergoing surgery for colorectal carcinoma in the presence of synchronous PC. METHODS: Patients diagnosed with primary colorectal cancer and synchronous PC in three community hospitals were selected from the Eindhoven Cancer Registry database. Outcomes of postoperative complications, in-hospital mortality and overall survival were collected and analyzed according to the type of intervention performed. RESULTS: Between 1995 and 2009, 169 colorectal cancer patients were diagnosed with synchronous PC, most of them unexpectedly during surgery (n = 130). 142 patients underwent surgery: primary tumor resection (n = 91), palliative procedure (n = 46) or exploration only (n = 5). In-hospital mortality was 41% after palliative surgery and 14% after primary tumor resection. Median survival was 12 weeks after palliative surgery or exploration as opposed to 55 weeks after primary tumor resection. CONCLUSION: PC is most often encountered unexpectedly during surgery for colorectal cancer. Results of palliative procedures are very poor with a high in-hospital mortality rate and short survival. Resection of the primary tumor can be performed safely with relatively good outcomes but some patients could have benefited from an even more radical approach when the presence of PC would have been diagnosed at an earlier stage. Improvement of imaging techniques to detect PC prior to surgery is therefore urgently needed. Until this is the case, a high index of suspicion is required when subtle signs of PC are encountered.

Intraoperative radiotherapy and cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. Five consecutive case reports of locally advanced rectal cancer with synchronous peritoneal carcinomatosis.

PURPOSE: Treatment of rectal cancer has markedly improved since the introduction of neoadjuvant strategies and better surgical techniques. However, treatment remains troublesome for patients with locally advanced rectal cancer (LARC) or with peritoneal carcinomatosis (PC). Patients presenting with LARC may now benefit from the integration of intra-operative radiotherapy (IORT) into multimodality treatment. Selected patients with PC now undergo cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) resulting in improved survival. Some patients present with locally advanced disease and synchronous peritoneal carcinomatosis and fulfill the eligibility criteria for both HIPEC and IORT, raising the question whether the combined application of both modalities within one operative procedure is feasible. CASE SERIES: This report includes five consecutive cases of rectal cancer patients presenting with LARC and synchronous PC who were treated with a multimodality treatment including IORT and HIPEC after cytoreductive surgery. Postoperative complications and survival are described. RESULTS: The combination of cytoreductive surgery with HIPEC and IORT appeared to be feasible and well tolerated. The observed complications did not differ from the morbidity associated with extensive pelvic surgery without HIPEC or IORT. No inhospital mortality occurred. One patient died after 11 months of recurrent disease. All other patients are currently alive with one patient already surviving 38 months. CONCLUSION: The current case series shows that a multimodality treatment containing IORT and HIPEC is feasible and safe with promising survival rates. This strategy may, therefore, be considered in selected rectal cancer patients presenting with both LARC and synchronous PC.

Outcomes of colorectal cancer patients with peritoneal carcinomatosis treated with chemotherapy with and without targeted therapy.

BACKGROUND: Although systemic therapies have shown to result in survival benefit in patients with metastatic colorectal cancer (mCRC), outcomes in patients with peritoneal carcinomatosis (PC) are poor. No data are available on outcomes of current chemotherapy schedules plus targeted agents in mCRC patients with PC. METHODS: Previously untreated mCRC patients treated with chemotherapy in the CAIRO study and with chemotherapy and targeted therapy in the CAIRO2 study were included and retrospectively analysed according to presence or absence of PC at randomisation. Patient demographics, primary tumour characteristics, progression-free survival (PFS), overall survival (OS), and occurrence of toxicity were evaluated. RESULTS: Thirty-four patients with PC were identified in the CAIRO study and 47 patients in the CAIRO2 study. Median OS was decreased for patients with PC compared with patients without PC (CAIRO: 10.4 versus 17.3 months, respectively (p ≤ 0.001); CAIRO2: 15.2 versus 20.7 months, respectively (p < 0.001)). Median number of treatment cycles did not differ between patients with or without PC in both studies. Occurrence of major toxicity was more frequent in patients with PC treated with sequential chemotherapy in the CAIRO study as compared to patients without PC. This was not reflected in reasons to discontinue treatment. In the CAIRO2 study, no differences in major toxicity were observed. CONCLUSION: Our data demonstrate decreased efficacy of current standard chemotherapy with and without targeted agents in mCRC patients with PC. This suggests that the poor outcome cannot be explained by undertreatment or increased susceptibility to toxicity, but rather by relative resistance to treatment.

Population-based survival of patients with peritoneal carcinomatosis from colorectal origin in the era of increasing use of palliative chemotherapy.

BACKGROUND: Palliative chemotherapy improves survival in patients with metastasised colorectal cancer. However, there is a lack of data regarding the effectiveness of modern chemotherapy in patients with isolated peritoneal carcinomatosis (PC). PATIENTS AND METHODS: All patients with synchronous PC of colorectal origin diagnosed in the Eindhoven Cancer Registry registration area between 1995 and 2008 were included (N = 904). We assessed the use of chemotherapy and overall survival in three time periods related to the availability of different chemotherapy regimens. RESULTS: Chemotherapy use gradually increased over time. Median survival (MS) for patients with PC without other metastases diagnosed in 1995-2000 was 35 weeks [95% confidence interval (CI) 24-43] and 34 weeks (25-54) in 2005-2008. MS in patients diagnosed with PC plus other metastases was 21 weeks (15-27) in 1995-2000 and 26 weeks (18-33) in 2005-2008. In multivariable regression analysis, use of chemotherapy had a beneficial influence on survival only in 2005-2008. In the first two periods, chemotherapy treatment did not decrease the risk for death. CONCLUSION: Despite increasing usage of palliative chemotherapy and availability of new agents, population-based survival of patients with PC did not improve until very recently. Response to palliative chemotherapy in PC should be evaluated separately from haematogenous metastases.

Intraoperative hyperthermic intraperitoneal chemotherapy after cytoreductive surgery for peritoneal carcinomatosis in an experimental model.

BACKGROUND: The combination of cytoreductive surgery (CS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is the treatment of choice for selected patients with peritoneal carcinomatosis (PC) of colorectal origin. However, it remains to be proven whether the addition of HIPEC to CS is essential for the reported survival benefit. METHODS: Sixty WAG/Rij rats were inoculated intraperitoneally with the rat colonic carcinoma cell line CC-531. Animals were randomized into three treatment groups: CS alone, CS followed by HIPEC (mitomycin 15 mg/m(2) ) and CS followed by HIPEC (mitomycin 35 mg/m(2) ). Survival was the primary outcome parameter. RESULTS: The median survival of rats treated with CS alone was 43 days. Rats receiving HIPEC 15 mg/m(2) and HIPEC 35 mg/m(2) both had a significantly longer median survival of 75 days (P = 0·003) and 97 days (P < 0·001) respectively. Rats receiving HIPEC showed a significantly lower tumour load at autopsy compared with rats treated with CS alone. CONCLUSION: A combination of CS and HIPEC results in longer survival than CS alone in rats with PC of colorectal origin.

Omentoplasty in rectal cancer surgery prolongs post-operative ileus.

BACKGROUNDS AND AIM: Omentoplasty is frequently used as a safeguard in rectal cancer surgery for wrapping the anastomosis or filling up the pelvic cavity. The omentum is known for its infection defence and haemostatic and angiogenic properties. A disadvantage was hypothesized to be prolonged post-operative ileus, as omentoplasty interrupts the blood flow from an epiploic artery to the stomach. MATERIALS AND METHODS: Patients who had had an uncomplicated surgical treatment for primary rectal cancer between January 2006 and March 2007 were included. Clinical parameters of post-operative ileus were collected and compared between procedures with a concomitant omentoplasty (n = 31) and without (n = 20). RESULTS: Patients needed their gastric tube significantly longer after omentoplasty than those without (3.9 vs 1.6 days, p < 0.001). Similar significant results were found for time to normal diet (p = 0.004), time to first discharge of faeces (p = 0.007), need for parenteral feeding (p = 0.036) and length of hospital stay (p = 0.008). Furthermore, there was a non-significant trend for more days to first discharge of air (3.4 vs 2.4 days, p = 0.165). There were no significant differences in patients' and procedure characteristics, except for more low anterior resections in the group without an omentoplasty (p < 0.001). None of these characteristics had any clinically relevant interference with the parameters of post-operative ileus. CONCLUSION: A trend for prolonged post-operative ileus was found in patients who underwent an omentoplasty concomitant with their treatment for primary rectal cancer. When assessing the importance of omentoplasty in the future, post-operative ileus should be taken into account.