Intraoperative electron beam radiotherapy and perioperative high-dose-rate brachytherapy in previously irradiated oligorecurrent gynecological cancer: clinical outcome analysis

Background Pelvic recurrences from previously irradiated gynecological cancer lack solid evidence for recommendation on salvage. Methods A total of 58 patients were included in this clinical analysis. Salvage surgery was performed for locoregional relapse within previously irradiated pelvic area after initial surgery and adjuvant radiotherapy or radical external beam radiotherapy. The primary tumor diagnosis included cervical cancer (n = 47, 81%), uterine cancer (n = 4, 7%), and other types (n = 7, 12%). Thirty-three patients received adjuvant IOERT (1984–2000) at a median dose of 15 Gy (range 10–20 Gy) and 25 patients received adjuvant PHDRB (2001–2016) at a median dose of 32 Gy (range 24–40 Gy) in 6, 8, or 10 b.i.d. fractions. Results The median follow-up was 5.6 years (range 0.5–14.2 years). Twenty-nine (50.0%) patients had positive surgical margins. Grade ≥ 3 toxic events were recorded in 34 (58.6%) patients. The local control rate at 2 years was 51% and remained stable up to 14 years. Disease-free survival rates at 2, 5, and 10 years were 17.2, 15.5, and 15.5%, respectively. Overall survival rates at 2, 5, and 10 years were 58.1, 17.8, and 17.8%, respectively. Conclusions IOERT and PHDRB account for an effective salvage in oligorecurrent gynecological tumors. Patients with previous pelvic radiation suitable for salvage surgery and at risk of inadequate margins could benefit from adjuvant reirradiation in form of IOERT or PHDRB. However, the rate of severe grade ≥ 3 toxicity associated with the entire treatment program is relevant and needs to be closely counterbalanced against the expected therapeutic gain (AU)

Intraoperative electron beam radiotherapy and perioperative high-dose-rate brachytherapy in previously irradiated oligorecurrent gynecological cancer: clinical outcome analysis.

BACKGROUND: Pelvic recurrences from previously irradiated gynecological cancer lack solid evidence for recommendation on salvage. METHODS: A total of 58 patients were included in this clinical analysis. Salvage surgery was performed for locoregional relapse within previously irradiated pelvic area after initial surgery and adjuvant radiotherapy or radical external beam radiotherapy. The primary tumor diagnosis included cervical cancer (n = 47, 81%), uterine cancer (n = 4, 7%), and other types (n = 7, 12%). Thirty-three patients received adjuvant IOERT (1984-2000) at a median dose of 15 Gy (range 10-20 Gy) and 25 patients received adjuvant PHDRB (2001-2016) at a median dose of 32 Gy (range 24-40 Gy) in 6, 8, or 10 b.i.d. fractions. RESULTS: The median follow-up was 5.6 years (range 0.5-14.2 years). Twenty-nine (50.0%) patients had positive surgical margins. Grade ≥ 3 toxic events were recorded in 34 (58.6%) patients. The local control rate at 2 years was 51% and remained stable up to 14 years. Disease-free survival rates at 2, 5, and 10 years were 17.2, 15.5, and 15.5%, respectively. Overall survival rates at 2, 5, and 10 years were 58.1, 17.8, and 17.8%, respectively. CONCLUSIONS: IOERT and PHDRB account for an effective salvage in oligorecurrent gynecological tumors. Patients with previous pelvic radiation suitable for salvage surgery and at risk of inadequate margins could benefit from adjuvant reirradiation in form of IOERT or PHDRB. However, the rate of severe grade ≥ 3 toxicity associated with the entire treatment program is relevant and needs to be closely counterbalanced against the expected therapeutic gain.

Immune mechanisms mediating abscopal effects in radioimmunotherapy.

Radiotherapy of cancer has been traditionally considered as a local therapy without noticeable effects outside the irradiated fields. However, ionizing radiation exerts multiple biological effects on both malignant and stromal cells that account for a complex spectrum of mechanisms beyond simple termination of cancer cells. In the era of immunotherapy, interest in radiation-induced inflammation and cell death has considerably risen, since these mechanisms lead to profound changes in the systemic immune response against cancer antigens. Immunotherapies such as immunomodulatory monoclonal antibodies (anti-PD-1, anti-CTLA-4, anti-CD137, anti-OX40, anti-CD40, anti-TGFß), TLR-agonists, and adoptive T-cell therapy have been synergistically combined with radiotherapy in mouse models. Importantly, radiation and immunotherapy combinations do not only act against the irradiated tumor but also against distant non-irradiated metastases (abscopal effects). A series of clinical trials are exploring the beneficial effects of radioimmunotherapy combinations. The concepts of crosspriming of tumor neoantigens and immunogenic cell death are key elements underlying this combination efficacy. Proinflamatory changes in the vasculature of the irradiated lesions and in the cellular composition of the leukocyte infiltrates in the tumor microenvironment contribute to raise or dampen cancer immunogenicity. It should be stressed that not all effects of radiotherapy favor antitumor immunity as there are counterbalancing mechanisms such as TGFß, and VEGFs that inhibit the efficacy of the antitumor immune response, hence offering additional therapeutic targets to suppress. All in all, radiotherapy and immunotherapy are compatible and often synergistic approaches against cancer that jointly target irradiated and non-irradiated malignant lesions in the same patient.

[Stereotactic radiation therapy]. / Radioterapia estereotáctica.

Stereotactic radiotherapy is a form of external radiotherapy that employs a system of three dimensional coordinates independent of the patient for the precise localisation of the lesion. It also has the characteristic that the radiation beams are conformed and precise, and converge on the lesion, making it possible to administer very high doses of radiotherapy without increasing the radiation to healthy adjacent organs or structures. When the procedure is carried out in one treatment session it is termed radiosurgery, and when administered over several sessions it is termed stereotactic radiotherapy. Special systems of fixing or immobilising the patient (guides or stereotactic frames) are required together with radiotherapy devices capable of generating conformed beams (lineal accelerator, gammaknife, cyberknife, tomotherapy, cyclotrons). Modern stereotactic radiotherapy employs intra-tumoural radio-opaque frames or CAT image systems included in the irradiation device, which make possible a precise localisation of mobile lesions in each treatment session. Besides, technological advances make it possible to coordinate the lesion's movements in breathing with the radiotherapy unit (gating and tracking) for maximum tightening of margins and excluding a greater volume of healthy tissue. Radiosurgery is mainly indicated in benign or malign cerebral lesions less than 3-4 centimetres (arteriovenous malformations, neurinomas, meningiomas, cerebral metastases) and stereotactic radiotherapy is basically administered in tumours of extracraneal localisation that require high conforming and precision, such as inoperable early lung cancer and hepatic metastasis.

Analysis of POSSUM score and postoperative morbidity in patients with rectal cancer undergoing surgery.

BACKGROUND: The Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (POSSUM) and later modifications (P-POSSUM y CR-POSSUM) have been used to predict morbidity and mortality rates among patients with rectal cancer undergoing surgery. These calculations need some adjustment, however. The aim of this study was to assess the applicability of POSSUM to a group of patients with rectal cancer undergoing surgery, analysing surgical morbidity by means of several variables. METHODS: between January 1995 and December 2004, 273 consecutive patients underwent surgery for rectal cancer. Information was gathered about the patients, tumour and therapy. To assess the prediction capacity of POSSUM, subgroups for analysis were created according to variables related to operative morbidity and mortality. RESULTS: The global morbidity rate was 23.6% (31.2% predicted by POSSUM). The mortality rate was 0.7% (6.64, 1.95 and 2.08 predicted by POSSUM, P-POSSUM and CR-POSSUM respectively). POSSUM predictions may be more accurate for patients younger than 51 years, older than 70 years, with low anaesthetic risk (ASA I/II), DUKES stage C and D, surgery duration of less than 180 minutes and for those receiving neoadjuvant therapy. CONCLUSION: POSSUM is a good instrument to make results between different institutions and publication comparable. We found prediction errors for some variables related to morbidity. Modifications of surgical variables and specifications for neoadjuvant therapy as well as physiological variables including life style may improve future prediction of surgical risk. More research is needed to identify further potential risk factors for surgical complications.

A single prior course of BCNU-cisplatin chemotherapy has a significant deleterious effect on mobilization kinetics of otherwise untreated patients.

Extensive prior treatment with cytotoxic agents is associated with impaired mobilization of hematopoietic cells. To assess the effect of a single course of standard-dose chemotherapy (CT), we compared the results of filgrastim-induced mobilization among two sequential groups of grade III-IV malignant glioma patients included in a hematopoietic transplantation program. The first group (21 patients) had never been treated with CT until 2 days after surgery, when they received a course of 100 mg/m2 BCNU (i.v.) and 100 mg intracarotid cisplatin for cytoreduction (not for mobilization). At 1 month after this CT, they were mobilized with 12 microg/kg filgrastim. The second group (22 patients) was mobilized with the same dose of filgrastim directly after the surgery, without having ever received any prior CT. The blood level of CD34+ cells was significantly lower in the CT-treated patients, both on the fourth day of filgrastim (15 vs 36 cells x 10(6)/l; P=0.01) and on the fifth (25 vs 58 cells x 10(6)/l; P=0.003), as it was the number of CD34+ cells collected per apheresis (1.3 vs 3.5 x 10(6)/l; P<0.0005). The toxic effect of a single course of BCNU-cisplatin CT led to significant impairment of the filgrastim-induced mobilization response.

Intraoperative electron beam radiotherapy during radical surgery for locally advanced and recurrent cervical cancer.

OBJECTIVE: The goal of this study was to determine the toxicity patterns and clinical usefulness of intraoperative electron beam radiotherapy (IOERT) in patients with unfavorable-outcome cervical cancer. METHODS: From January 1986 to June 1999, 67 patients (36 recurrent, 31 primary disease) were treated with IOERT. Previously unirradiated patients received preoperative chemoradiation to 45 Gy with cisplatin 20 mg/m(2) and 5-fluorouracil 1000 mg/m(2). IOERT median dose was 12 Gy for primary disease (range: 10-25) and 15 Gy for recurrent disease (range: 10-20). RESULTS: The 10-year control rate within the area treated with IOERT ("in-field" (IF)) for the entire group was 69.4, with 92.8 and 46.4% 10-year IF control rates for the primary and recurrent patients, respectively. IF control rate correlated with involvement of the parametrial margin (P = 0.001), amount of residual disease (P = 0.001), and pelvic lymph node involvement (P = 0.032). The overall incidence of toxic events that might be attributable to IOERT was 14.9%. Chronic pain was observed in 8 of 67 evaluable patients (11.9%) and motor neuropathy of the lower extremity in one patient (3.2%). CONCLUSIONS: IOERT is a valuable boosting technique in the management of advanced but resectable cervical cancer. Patients, especially recurrent cases, with positive lymph nodes, parametrial involvement, and/or incomplete resections have poor local control rates despite IOERT at the doses used in this study.

[Effect of PSA nadir and the time to nadir in the disease-free period in localized prostatic carcinoma treated with radical radiation]. / Influencia del nadir de PSA y el tiempo a nadir en el periodo libre de enfermedad (PLE) del carcinoma prostático localizado tratado con irradiación radical.

OBJECTIVE: To evaluate the prognostic significance of PSA nadir (nPSA) and the time to nadir in disease free of recurrence (DFR) in localized carcinoma of prostate treated with radical radiotherapy (RTR). MATERIAL AND METHODS: From October 1984 to December 1998, 86 patients have been treated with prostate carcinoma. It was considered of Low risk those patients with PSA < or = 10 ng/ml, Gleason = 6 or stage T1-T2. Moderate risk: those with one elevated of the three parameters. High risk: two or more parameters. The treatment was carried out in a lineal accelerator using photons of 15 MV, with standard technique and frationation, administering a median dose of 66 Gy (58-75 Gy). It was defined disease free of recurrence (DFR), the time to clinical PSA or biochemical failure. This one was defined as the time starting from the date of nadir PSA to the second consecutive increase of PSA value after three separate serial measurements separated for at least one month. RESULTS: The median of initial PSA value was of 16 ng/ml (1-270), initial clinical stage T1-T2 (70p), stages T3-T4 (14p), and unknown in 2p. The median of Gleason score was 6 (2-10). According to the group of risk they were classified as: low risk in 16 patients (19%), moderated risk in 22 patients (26%), high risk in 21 patients (24%), and unknown in 27 patients (31%). Median nPSA value was 0.8 ng/ml (limits: 0-139) and the median time elapsed between the initial PSA and nPSA has been of 11 months (limits: 0-72 months). The actuarial DFR projected to five years in those patients with nPSA = 1 ng/ml was of 67% vs. 47% in patient with nPSA figures > 1 ng/ml (p = 0.0018). The PFD in patients with time to nadir (t nadir) < 12 months it was of 20% vs. 80% in patients with t nadir > 12 months (p < 0.0001). Multivariate analysis demonstrated that time to nadir (H.R: 0.11 p = 0.001), group of risk (H.R: 28.72 p = 0.020), and grade of differentiation (HR: 28.72 p = 0.010), were determinant to DFR. CONCLUSIONS: nPSA is an important factor to determine the objective response to radiotherapy. nPSA and time to nadir are prognostic factors that influences significantly on the DFR. The indication of adjuvant treatment in those patients with unfavorable prognostic factors such us those who do not reach nadir PSA < or = 1 ng/ml and time to nadir < or = 12 months, deserves the realization of a prospective study.

Influencia del nadir de PSA y el tiempo a nadir en el periodo libre de enfermedad (pie) del carcinoma prostatico localizado tratado con irradiación radical / Prognostic significance of PSA nadir and the time to nadir in disease free of recurrence in localized carcinoma of prostate treated with radical radiotherapy

Objetivo: Valorar el significado pronóstico del nadir de PSA (nPSA) y del tiempo a nadir en el periodo libre de enfermedad (PLE) del carcinoma de próstata localizado tratado con radioterapia radical (RTR). Material y métodos: Desde Octubre 1984 hasta Diciembre 1998 se han tratado 86 (p) con el diagnóstico de carcinoma de próstata. Se consideró de Bajo riesgo aquellos pacientes con PSA 1 ng/ml (p= 0,0018). El PLE a 5 años en pacientes con tiempo a nadir (t nadir) 12 meses (p<0,0001). El estudio multivariado demostró diferencias estadísticamente significativas para factores como tiempo t nadir (H.R: 0,11 p=0,001), grupos de riesgo (H.R: 28,72 p=0,020), y grado de diferenciación (HR: 28,72 p=0,010).Conclusiones: El nPSA es un factor importante para determinar la respuesta objetiva a la RT. El nPSA y t nadir son factores pronósticos que influyen significativamente sobre el PLE. La indicación de un tratamiento complementario en aquellos pacientes con factores pronósticos desfavorables como en el grupo que no llega a un nadir<= 1 ng/ml y en aquellos con tnadir menor de doce meses, merece la realización de un estudio prospectivo (AU)

Induction platinum-based chemotherapy followed by radical hyperfractionated radiotherapy with concurrent chemotherapy in the treatment of locally advanced non-small-cell carcinoma of the lung.

This study evaluated tolerance, local control, and short-term survival in patients with locally advanced non-small-cell lung carcinoma treated with induction chemotherapy followed by radical hyperfractionated radiotherapy with concurrent chemotherapy. Thirty-one patients with stage IIIa (N2) or IIIb tumors were treated with cis-platinum-based induction chemotherapy for 1 to 4 courses followed by radical hyperfractionated radiotherapy (69.6 Gy) with concurrent chemotherapy given at the beginning and end of radiotherapy. Induction chemotherapy produced no complete responses and 18 (58%) partial responses. After completion of radiotherapy, 4 patients had complete response (13%) and 23 patients (74%) partial response. The patterns of failure were as follows: intrathoracic, 6 patients (22%); intrathoracic + distant metastasis, 6 patients (22%); distant metastasis without thoracic failure, 5 patients (19%). Six patients of the 12 with intrathoracic failure experienced in-field radiotherapy pure local failure. At the time of this analysis, 10 patients were alive and well (4 complete and 6 partial responders). Actuarial survival projected at 39 months is 35%. No benefit was observed for those patients responding to induction chemotherapy. Toxicity was as follows: grade III neutropenic fever in 4 patients (13%), grade IV neutropenia in 13 patients (42%), pneumonia in 6 patients (19%), grade III esophagitis in 4 patients (13%) and severe clinical pneumonitis in 1 patient (3%). Induction chemotherapy followed by chemoradiotherapy is feasible, and the preliminary results are encouraging. Complete response after radiotherapy appeared to be related to short-term disease-free survival, and decisions based on the response to chemotherapy may be equivocal.

Patterns of failure and long-term results in high-risk resected gastric cancer treated with postoperative radiotherapy with or without intraoperative electron boost.

BACKGROUND: To evaluate the possible role of adjuvant radiotherapy in the management of high-risk resected gastric carcinoma. METHODS: From 1982 to 1993, 62 patients surgically resected of a primary gastric cancer with adverse pathological features (serosal and/or regional lymph node involvement) were treated with postoperative radiotherapy with (Group I) or without (Group II) intraoperative electron boost to the surgical bed and coeliac axis (IORT). RESULTS: After a median follow-up of 75.6 months (range 4-120+) for IORT patients and 91.2 months (range 6-149+) for non-IORT patients, overall relapse rates for Group I and Group II patients were 44.5% and 48.6% and local-regional relapse rates were 11.1% and 20%, respectively. Actuarial survival rates projected at the maximum follow-up were 41% and 38% in Groups I and II, respectively. CONCLUSIONS: This retrospective analysis suggests a beneficial effect of adjuvant external radiotherapy in promoting local-regional control in high-risk resected gastric cancer.

High-dose BCNU and autologous progenitor cell transplantation given with intra-arterial cisplatinum and simultaneous radiotherapy in the treatment of high-grade gliomas: benefit for selected patients.

A phase II study of postoperative high-dose carmustine (HDBCNU), intracarotid cisplatin (CDDP), and radical radiotherapy in patients with high-grade glioma was performed. Patients underwent 4-6 consecutive days of blood hematopoietic progenitor cell (HPC) apheresis without prior mobilization. Chemotherapy included intracarotid CDDP, 60 mg/m2, and BCNU, 900 mg/m2. HPC were infused 48 h after HDBCNU. Whole brain irradiation, up to 50 Gy, was started on the 8th day after HPC infusion. With a median follow-up time of 44 months, median overall survival was 15.5 months. Eight patients (23.5%) are alive free of disease 2-6 years after treatment (seven out of 25 patients with glioblastoma multiforme and one out of nine patients with anaplastic astrocytoma). Survival was influenced by young age, good performance and complete surgical resection. Two patients (5.8%) died of therapy-related complications. Acute hematological toxicity of HDBCNU was moderate, with a full recovery on day 26. No acute pulmonary or hepatic toxicity was found. Late severe neurological toxicity was observed in one third of patients surviving beyond 2 years. We conclude that HDBCNU, 900 mg/m2, intracarotid CDDP and radical radiotherapy appear to benefit some patients with high-grade gliomas, and phase III studies should preferentially select young patients with resectable tumors.

Combined treatment in superior sulcus tumors.

From January 1988 to August 1992, 18 patients (pts) with the established diagnosis of non-small cell lung cancer of the superior sulcus have been treated with a multidisciplinary approach, which includes 1-3 cycles of neoadjuvant chemotherapy (MVP or MCP regimens) followed by simultaneous preoperative chemotherapy and external beam irradiation. Radical surgery plus intraoperative radiotherapy (IORT) was planned 4-5 weeks after the end of the preoperative protocol. Tumor stages were IIIA (9 pts) and IIIB (9 pts). Tumor characteristics included rib and vertebral involvement in 15 and 4 pts, respectively. Fatal toxicity was present in 3 pts (16.6%). Resectability rate was 76.4%. Pathologic findings disclosed complete response (pT0) in 70.5% of the surgical specimens and viable tumor (pT+) in 29.5%. With a median follow-up of 24+ months (2-52+), 4-year actuarial local control, and overall survival rates are 91% and 56.2%, respectively. Four-year actuarial overall survival according to pathologic response was 87.5% for pT0 patients and 20% for pT+ patients. We conclude that this regimen promotes a high rate of pT0 as well as better than expected local control and survival rates. The presence of a pT0 specimen seems to correlate with the patient outcome.

Intraoperative radiotherapy in recurrent gynecological cancer.

A retrospective analysis to assess the feasibility and clinical tolerance of intraoperative radiotherapy (IORT) in the treatment of recurrent gynecologic cancer is reported. From February 1985 to September 1992, 26 patients with recurrent gynecologic tumors entered this trial. The clinical experience comprises two different categories of disease situations: tumors relapsing after full dose radiation therapy (group I) and recurrent disease to previous surgery (group II). Cervical carcinoma was the initial tumor site of involvement in 18 patients (69%). Treatment consisted in maximal surgical resection + IORT boost (10-25 Gy) to the high-risk areas for recurrence. Non previously irradiated patients also received external beam irradiation (EBRT) (+/- chemotherapy) pre- or postoperatively. IORT-related toxicity was one episode of motor neuropathy. Local control rates have been 33% and 77%, respectively in groups I and II. The 4-year actuarial overall survival in Group I is 7% and 6-year actuarial overall survival in Group II is 33%. The addition of IORT to surgical debulking achieves modest local control and long-term survival rates if tumor-free margins cannot be obtained in previously irradiated patients. Combined EBRT (+/- chemotherapy) maximal surgical resection plus IORT could render some long-term survivors among those surgical recurrent patients not candidates for radical surgery with curative intent.

Intraoperative and external preoperative radiotherapy in invasive bladder cancer: effect of neoadjuvant chemotherapy in tumor downstaging.

Absence of residual cancer (pT0) in the cystectomy specimen was evaluated in patients with invasive bladder cancer treated with intraoperative (IORT) (15 Gy) and preoperative external beam radiotherapy (EBR) (46 Gy/5 weeks) with or without neoadjuvant chemotherapy. The overall pT0 rate was 68% (67% and 70% in patients with or without neoadjuvant chemotherapy, respectively). The tolerance to the program was acceptable in both groups. It is concluded that intense, combined modality treatment is feasible in bladder cancer patients, and the addition of neoadjuvant chemotherapy does not increase the morbidity. Preliminary results on disease-free survival are encouraging.

Intraoperative and external radiotherapy in resected gastric cancer: updated report of a phase II trial.

From September 1984 to August 1991, 48 evaluable patients with resected gastric cancer and apparent disease confined to locoregional area were treated with intraoperative electron beam boost to the celiac axis and peripancreatic nodal areas (15 Gy) and external irradiation (40 to 46 Gy in 4 to 5 weeks) including the gastric bed and upper abdominal nodal draining regions. At the time of evaluation for IORT, the disease was primary in 38 cases, recurrent but resectable in four (anastomosis), and unresectable in four (nodal). Post operative complications were reversible. Acute tolerance to the complete treatment program was acceptable. Late complications included life-threatening events: Six episodes of gastro intestinal bleeding (three of them had an arteriographic documentation of arterioenteric fistula) and nine with severe enteritis (five required reoperation). Other long-term treatment related complications were six cases of vertebral collapse. The median follow-up time for the entire group is 22 months. Locoregional recurrence/persistence of disease has been identified in five patients (three with residual and/or recurrent postsurgical tumor). Systemic tumor progression has been detected in 15 patients (11 in intra-abdominal sites). Overall actuarial survival for patients with positive or negative serosal involvement was 33% versus 56%. It is concluded that the treatment program described is able to induce a high locoregional tumor control rate (100%) when used strictly in an adjuvant setting and might control long term, a small portion of patients not amenable for curative surgery (2 out of 8 patients with confirmed residual post-surgical disease). Gastrointestinal bleeding and enteritis are findings that indicate treatment intensity at the upper limits of tissue tolerance. Assessment of long term tolerance of pancreatic parenchyma and large blood vessels (tissues included in the IRORT field) are pending for longer follow-up and the appropriate selective studies.