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Carbon-Ion Radiation Therapy for Pelvic Recurrence of Rectal Cancer.

PURPOSE: Investigation of the treatment potential of carbon-ion radiation therapy in pelvic recurrence of rectal cancer. METHODS AND MATERIALS: A phase 1/2 dose escalation study was performed. One hundred eighty patients (186 lesions) with locally recurrent rectal cancer were treated with carbon-ion radiation therapy (CIRT) (phase 1/2: 37 and 143 patients, respectively). The relapse locations were 71 in the presacral region, 82 in the pelvic sidewalls, 28 in the perineum, and 5 near the colorectal anastomosis. A 16-fraction in 4 weeks dose regimen was used, with total dose ranging from 67.2 to 73.6 Gy(RBE); RBE-weighted absorbed dose: 4.2 to 4.6 Gy(RBE)/fraction. RESULTS: During phase 1, the highest total dose, 73.6 Gy(RBE), resulted in no grade >3 acute reactions in the 13 patients treated at that dose. Dose escalation was halted at this level, and this dose was used for phase 2, with no other grade >3 acute reactions observed. At 5 years, the local control and survival rates at 73.6 Gy(RBE) were 88% (95% confidence interval [CI], 80%-93%) and 59% (95% CI, 50%-68%), respectively. CONCLUSION: Carbon-ion radiation therapy may be a safe and effective treatment option for locally recurrent rectal cancer and may serve as an alternative to surgery.

Use of Inflated Foley Catheters to Prevent Early Empty Pelvis Complications Following Pelvic Exenteration.

For most patients with bulky pelvic tumors, pelvic exenteration remains the only curative option. Although initially reported as a palliative procedure, nowadays it is rather performed with curative intent. Once the resectional phase is ended, a large defect will remain at the level of the pelvic diaphragm, predisposing to severe complications which are generically included under the name of empty pelvis syndrome. It has been widely demonstrated that this type of complication is associated with severe mortality, even if the patient is free of any pelvic recurrence. We present the case of a 56-year-old patient submitted to total pelvic exenteration for locally invasive previously chemo-irradiated cervical cancer who presented six months after surgery with a severe enteroperineal fistula. We decided to reoperate on the patient; intraoperatively we found recurrence on both pelvic walls and an enteroperineal fistula caused by tumoral invasion. We performed an intestinal resection with enteroenteral anastomosis. In order to isolate the intestinal loops from the unresectable pelvic recurrence, in the pelvis we placed three Foley catheters inflated with 60 ml of saline each, in order to hold the intestinal loops away from the pelvic wall. The postoperative course was uneventful. The urinary cathethers were removed after six weeks.

MTDH/AEG-1-based DNA vaccine suppresses metastasis and enhances chemosensitivity to paclitaxel in pelvic lymph node metastasis.

OBJECTIVE: MTDH/AEG-1 could act as an oncogene by regulating cellular transformation, proliferation, invasion, metastasis, and angiogenesis. This study aims to explore the mechanism by which MTDH/AEG-1 inhibits cancer growth and metastasis and enhances chemosensitivity. METHODS: Mouse model was established using orally immunized mice exposed to attenuated Salmonella containing vectors carrying full length MTDH/AEG-1 gene, and we were able to enhance the immune response and inhibit the growth and metastasis of prostate cancer through activation of cellular and humoral immunities and induction of CD8+ T cells. Immunohistochemistry and TUNEL assay, CD4+ and CD8+ T cell analysis by flow cytometry, HE staining, RT-PCR analysis, Western-blot analysis and quantitative polymerase chain reaction were performed. RESULTS: The MTDH/AEG-1 gene vaccine induced the anti-tumor function of cytotoxic T lymphocytes and CD8+ T cells and inhibited tumor growth and metastasis of prostate cancer. In the therapy model, the MTDH/AEG-1 gene vaccine significantly enhanced chemosensitivity to paclitaxel, inhibited tumor growth, promoted tumor cell apoptosis, and prolonged the survival time of tumor-bearing mice without any apparent side effects. CONCLUSIONS: Our results demonstrated that MTDH/AEG-1-based DNA vaccines could used for the treatment of prostate cancer in terms of the inhibition of tumor growth, the lifespan of tumor-bearing animals. Combined with chemotherapy, MTDH/AEG-1-based DNA vaccines may produce highly favorable outcomes in the prevention and treatment of prostate cancer, suggesting the immune efficacy of MTDH/AEG-1-based DNA should be further analyzed in other cancers.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for management of recurrent/relapsed ovarian granulosa cell tumor: a single-center experience.

AIM: The aim of this study was to retrospectively report our experience (efficacy/morbidity) with cytoreductive surgery+hyperthermic intraperitoneal chemotherapy (CRS+HIPEC) for the management of recurrent/relapsed ovarian granulosa cell tumors (OGCT). MATERIAL AND METHODS: From 2010 to 2013, six patients underwent CRS+HIPEC. CRS was performed with standard peritonectomy procedures and visceral resections directed towards complete elimination of tumors from the abdominopelvic cavity. HIPEC was performed with cisplatin (50 mg/m²) and doxorubicin (15 mg/m²) and allowed to circulate in the abdominopelvic cavity for 90 min at 41.0-42.2°C. RESULTS: Cytoreduction completeness (CC-0) was achieved in all except one patient (CC-1). Five patients had OGCT recurrences in abdomen+pelvis and one patient in abdomen only. No grade V morbidity (Clavien-Dindo classification) occurred. Two patients developed lung atelectasis, which was managed by mere chest physiotherapy (grade I). One patient developed urinary tract infection (grade II) and another patient developed pneumonia (grade II) - both of which were managed by antibiotics. One patient developed splenic bed and anterior abdominal wall collections requiring ultrasound-guided aspiration without general anesthesia (grade III). One patient developed pulmonary embolism requiring intensive care-unit management (grade IV). Four chemo-naïve patients received adjuvant chemotherapy whereas the remaining two previously chemo-exposed patients received no adjuvant therapy. All patients were alive and disease-free without proof of recurrence/relapse at 40, 32, 27, 24, 20 and 16 months. The average interval of follow-up after CRS+HIPEC was roughly 27 months (range: 16-40 months). CONCLUSION: CRS+HIPEC appears to be an efficacious and morbidly well-tolerated therapeutic modality for recurrent/relapsed OGCT. Long-term follow-up data and further research are needed.

Risk of desmoid tumours after open and laparoscopic colectomy in patients with familial adenomatous polyposis.

BACKGROUND: Desmoid tumour (DT) is a main cause of death after prophylactic colectomy in patients with familial adenomatous polyposis (FAP). The purpose of this study was to evaluate the impact of prophylactic laparoscopic colectomy on the risk of developing DT in patients with FAP. METHODS: The database of a single institution was reviewed. Patients with classical FAP with defined genotype who underwent either open or laparoscopic colectomy between 1947 and 2011 were included in the study. The impact of various demographic and clinical features on the risk of developing DT was assessed. RESULTS: A total of 672 patients underwent prophylactic colectomy: 602 by an open and 70 by a laparoscopic approach. With a median (range) follow-up of 132 (0-516) months in the open group and 60 (12-108) months in the laparoscopic group, 98 patients (16·3 per cent) developed DT after an open procedure compared with three (4 per cent) following laparoscopic surgery. The estimated cumulative risk of developing DT at 5 years after surgery was 13·0 per cent in the open group and 4 per cent in the laparoscopic group (P = 0·042). In multivariable analysis, female sex (hazard ratio (HR) 2·18, 95 per cent confidence interval 1·40 to 3·39), adenomatous polyposis coli mutation distal to codon 1400 (HR 3·85, 1·90 to 7·80), proctocolectomy (HR 1·67, 1·06 to 2·61), open colectomy (HR 6·84, 1·96 to 23·98) and year of surgery (HR 1·04, 1·01 to 1·07) were independent risk factors for the diagnosis of DT after prophylactic surgery. CONCLUSION: Laparoscopic surgery decreased the risk of DT after prophylactic colectomy in patients with FAP.

Value of diffusion-weighted and gadolinium-enhanced MRI for the diagnosis of pelvic recurrence from colorectal cancer.

PURPOSE: To prospectively assess the added value of gadolinium-enhanced and diffusion-weighted (DWI) MRI for the diagnosis of pelvic recurrence from colorectal cancer (CRC). MATERIALS AND METHODS: Fifty-two patients with suspected pelvic recurrence from CRC underwent pelvic MRI with T2-weighted ("T2"), gadolinium-enhanced fat-suppressed T1-weighted ("gadolinium") and DWI MR sequences. Three readers (senior radiologist: R1, two residents: R2, R3) scored the likelihood of recurrence on "T2," "T2 + DWI," and "T2 + Gadolinium." RESULTS: Twenty-seven patients had 42 sites of pelvic recurrence. On "T2," R1 achieved AUC of .95, sensitivity 88.4%, specificity 95.2%. For R2, these figures were .89, 81.4%, 90.5%, for R3 .90, 83.7%, 76%. Both Gadolinium injection and DWI significantly improved AUCs for residents but not for the senior radiologist: up to .988 (R2, P = 0.006) and to .98 (R3, P = 0.01) with DWI and to .96 (R2, P = 0.04), .98 (R3, P = 0.01) after gadolinium. All readers achieved slightly better AUCs with "T2 + DWI" than with "T2+Gadolinium" but not significantly (P = 0.68, P = 0.11, P = 0.3; respectively). CONCLUSION: For diagnosis of pelvic recurrence from CRC, both DWI and gadolinium-enhanced MRI significantly increase diagnostic performances compared with "T2" MRI for residents. DWI may be helpful in patients with contra-indications to intravenous administration of gadolinium.

Patterns and signal intensity characteristics of pelvic recurrence of rectal cancer at MR imaging.

Magnetic resonance (MR) imaging is becoming the cross-sectional imaging modality of choice for follow-up of patients with previous rectal cancer to diagnose pelvic recurrence and plan for surgery. The authors conducted a retrospective review of MR imaging examinations performed at their institution for evaluation of local recurrence of rectal cancer in 42 patients. Twenty-six patients had undergone rectal anastomosis and 16 had undergone abdominoperineal resection. The mean interval between initial surgery and recurrence was 2.5 years. Recurrence sites were axial (involving the anastomosis) (n = 19); lateral (sidewall) (n = 6); anterior (prostate or seminal vesicle [n = 2], bladder [n = 4], ureter [n = 3], vagina or uterus [n = 5]); or posterior (presacral fascia [n = 11], sacrum [n = 2]). Other recurrence sites included the pelvic floor (n = 7), sciatic nerve (n = 2), obturator nerve (n = 1), perineum (n = 1), abdominal wall (n = 1), or adnexa (n = 1). Recurrence was confirmed at surgery or by evidence of tumor growth at follow-up imaging. Recurrence patterns, signal intensity characteristics, findings of unresectability, potential MR imaging pitfalls, and the role of MR imaging versus other modalities in evaluating recurrent rectal carcinoma are discussed. Supplemental material available at http://radiographics.rsna.org/lookup/suppl/doi:10.1148/rg335115170/-/DC1.

Endometrium is not the primary site of origin of pelvic high-grade serous carcinoma in BRCA1 or BRCA2 mutation carriers.

Serous endometrial intraepithelial carcinoma has been proposed to be a potential precursor lesion of pelvic high-grade serous carcinoma. If true, an increased incidence of uterine papillary serous carcinomas would be expected in BRCA1 and BRCA2 mutation carriers, who are at high-risk of developing pelvic high-grade serous carcinoma. This study explored particularly the occurrence of uterine papillary serous carcinoma, as well as other endometrial cancers, following risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 germline mutation attending a tertiary multidisciplinary clinic. A consecutive series of women with a BRCA1 or BRCA2 mutation who had undergone risk-reducing salpingo-oophorectomy without hysterectomy at the University Medical Center Groningen from January 1996 until March 2012 were followed prospectively. They were crossed with the histopathology list of endometrial cancer diagnoses reported by the Dutch nationwide pathology database PALGA. To assess the risk of endometrial cancer, a standardized incidence ratio was calculated comparing the observed with the expected number of endometrial cancer cases. Overall, 201 BRCA1 and 144 BRCA2 mutation carriers at a median age of 50 years (range, 32-78) were analyzed. After a median follow-up period of 6 years, after risk-reducing salpingo-oophorectomy, two cases of endometrial cancer were diagnosed, whereas the expected number was 0.94 cases (standardized incidence ratio 2.13; 95% confidence interval 0.24-7.69; P=0.27). Both endometrial cancer cases were of the endometrioid histological subtype. We showed that the incidence of endometrial cancer following risk-reducing salpingo-oophorectomy, especially uterine papillary serous carcinoma, in women at high-risk of developing pelvic high-grade serous carcinoma is not increased. On the basis of our data, the hypothesis of serous endometrial intraepithelial carcinoma being an important precursor lesion of pelvic high-grade serous carcinoma seems unlikely. There is no need to add a prophylactic hysterectomy to risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers.

The selective aryl hydrocarbon receptor modulator 6-methyl-1,3,8-trichlorodibenzofuran inhibits prostate tumor metastasis in TRAMP mice.

The aryl hydrocarbon receptor (AhR) is a basic-helix-loop-helix transcription factor that binds halogenated aromatic hydrocarbons, polycyclic aromatic hydrocarbons, and endogenous compounds. We previously reported that AhR null (Ahr(-/-)) transgenic adenocarcinoma of the mouse prostate (TRAMP) mice on a C57BL/6J background develop prostate tumors with much greater frequency than AhR wild-type (Ahr(+/+)) TRAMP mice, suggesting that the AhR has tumor suppressor properties. Because AhR signaling pathway inactivation increased susceptibility to prostate tumorigenesis, we tested the hypothesis that a selective AhR modulator (SAhRM), 6-methyl-1,3,8-trichlorodibenzofuran (6-MCDF), can protect against prostate tumorigenesis. TRAMP mice on the standard C57BL/6JxFVB genetic background were fed 0, 10, or 40mg 6-MCDF/kg diet beginning at 8 weeks of age. Tumor incidence, pelvic lymph node metastasis, and serum vascular endothelial growth factor (VEGF) concentrations were determined at 140 days of age. Prostate tumor incidence and size were not significantly reduced in mice fed 6-MCDF. However, the frequency of pelvic lymph node metastasis was reduced fivefold in mice fed the 40mg 6-MCDF/kg diet. Serum VEGF concentrations were also reduced by 6-MCDF treatment, particularly in mice without prostate tumors, and 6-MCDF was shown to act directly on cultured prostates to inhibit VEGF secretion. Together, these results suggest that 6-MCDF inhibits metastasis, in part, by inhibiting prostatic VEGF production prior to tumor formation. This is the first report that 6-MCDF can confer protection against prostate cancer in vivo.

[Study of prophylactic intra-iliac and hepatic arterial infusion chemotherapy against pelvic recurrence and liver metastasis after radical resection for rectal cancer].

OBJECTIVE: To study the effects of prophylactic intra-iliac and hepatic arterial infusion chemotherapy on pelvic recurrence and liver metastasis after radical resection for rectal cancer. METHODS: Eighty-four rectal cancer patients,undergone radical resection on Dukes stage B or C,were randomly assigned to postoperative intra-iliac and hepatic arterial infusion chemotherapy group(group I) and routine vein chemotherapy group(group II). Five-year survival and recurrence rates were compared between the two groups. RESULTS: Among the 84 rectal cancer patients with radical resection, the 5-year liver metastasis and pelvic recurrence rates were 30.2% (13/43) and 18.6% (8/43) respectively in group II, 17.1% (7/41) and 9.8% (4/41) in group I, the difference was significant between 2 groups (chi(2)=4.31, P<0.05). The mean tumor-free survival time was 26.2 months in group I and 15.8 months in group II (t=5.05, P<0.01), the difference was significant (t=5.05, P<0.01). The five-year survival rate in group I (65.9%) was significantly higher than that in group II (56.5%) (u=8.86, P<0.01). Cox multivariate analysis showed that, compared with those in group II, the relative risks of pelvic recurrence and liver metastasis in group I decreased 20% (coefficient of relative risk: 0.7959), and the five-year mortality also decreased 20% (coefficient of relative risk: 0.8034). CONCLUSION: Prophylactic intra-iliac and hepatic arterial infusion chemotherapy can reduce the rates of pelvic recurrence and liver metastasis after radical resection of rectal cancer.

On the apparent failure of adjuvant pelvic radiotherapy to improve survival for women with uterine sarcomas confined to the uterus.

Despite numerous studies documenting reduction of pelvic relapses after adjuvant pelvic radiotherapy stage I and II uterine sarcomas, improved survival remains unproven. This retrospective report analyzes patterns of failure, survival, and toxicity in 42 women with stage I and 7 patients with stage II uterine sarcomas treated from 1972 through 1998 to identify patients likely to benefit from pelvic or abdominal radiotherapy and chemotherapy. Four of these patients also received adjuvant chemotherapy. There were 20 leiomyosarcomas, 18 homologous mixed mullerian tumors, and 11 heterologous mixed mullerian tumors. Disease-free survivals for mixed mullerian tumors were 65% at 5 years and 61% at 15 years. Disease-free survivals for leiomyosarcomas were 40% at 5 years and 40% at 15 years. There were 14 distant only, 5 distant and abdominal, 1 abdominal, 1 distant and pelvic, and 2 unknown initial sites of failure. Acute toxicity was acceptable as measured by a median 1-kg weight loss from radiotherapy and a 2% rate of failure to complete therapy. Chronic toxicity consisted of 3 small bowel obstructions and 1 sigmoid colon obstruction. In conclusion, the efficacy of adjuvant pelvic radiation is demonstrated by the absence of any isolated pelvic failures. Although the frequent occurrence of peritoneal failures suggests a role for prophylactic abdominal radiation for mixed mullerian tumors, more effective systemic therapy is necessary to substantially increase the chance of cure for women with early-stage uterine sarcomas.

Significant pelvic recurrence in high-risk pathologic stage I--IV endometrial carcinoma patients after adjuvant chemotherapy alone: implications for adjuvant radiation therapy.

OBJECTIVE: To evaluate the risk of pelvic recurrence (PVR) in high-risk pathologic Stage I--IV endometrial carcinoma patients after adjuvant chemotherapy alone. METHODS: Between 1992 and 1998, 43 high-risk endometrial cancer patients received adjuvant chemotherapy. All patients underwent primary surgery consisting of total abdominal hysterectomy and bilateral salpingo-oophorectomy. No patients received preoperative radiation therapy (RT). Regional lymph nodes and peritoneal cytology were sampled in 62.8% and 83.7% of cases, respectively. Most patients had Stage III--IV disease (83.7%) or unfavorable histology tumors (74.4%). None had evidence of extra-abdominal disease. All patients received 4-6 cycles of chemotherapy as the sole adjuvant therapy, consisting primarily of cisplatin and doxorubicin. Recurrent disease sites were divided into pelvic (vaginal, nonvaginal) and extrapelvic (para-aortic, upper abdomen, liver, and extra-abdominal). Median follow-up was 27 months (range, 2--96 months). RESULTS: Twenty-nine women (67.4%) relapsed. Seventeen (39.5%) recurred in the pelvis and 23 (55.5%) in extrapelvic sites. The 3-year actuarial PVR rate was 46.5%. The most significant factors correlated with PVR were cervical involvement (CI) (p = 0.01) and adnexal (p = 0.05) involvement. Of the 17 women who developed a PVR, 8 relapsed in the vagina, 3 in the nonvaginal pelvis, and 6 in both. The 3-year vaginal and nonvaginal PVR rates were 37.8% and 26%, respectively. The most significant factor correlated with vaginal PVR was CI (p = 0.0007). Deep myometrial invasion (p = 0.02) and lymph nodal involvement (p = 0.03) were both correlated with nonvaginal PVR. Nine of the 29 relapsed patients (31%) developed PVR as their only (6) or first site (3) of recurrence. Factors associated with a higher rate of PVR (as the first or only site) were CI and Stage I--II disease. CONCLUSIONS: PVR is common in high-risk pathologic Stage I-IV endometrial cancer patients after adjuvant chemotherapy alone. These results support the continued use of locoregional RT in patients undergoing adjuvant chemotherapy. Further studies are needed to test the addition of chemotherapy to locoregional RT.

[Prevention of pelvic recurrence by preoperative radiochemotherapy and total mesorectal excision of rectal carcinoma?]. / Verhinderung pelviner Rezidive durch präoperative Radiochemotherapie und totale mesorektale Exzision des Rektumkarzinoms?

Preoperative radiotherapy (RT) alone or in combination with a pre- or postoperative chemotherapy reduces the recurrence rate and increases the survival rate for patients with resectable rectal cancer. The therapeutic index, i.e. relationship between effects and side effects is objective of studies. Especially toxicities to the small intestine and to the sphincter function are evaluated. Preoperative radiotherapy achieves the best results. The treatment volume includes the mesorectum in case of continence maintaining surgery and includes the anal sphincter in case of abdominoperineal resection. To exclude the small intestine from the RT-field, we prefer the use of 3 or 4 field technique in a prone position with filled bladder, using an optimal field limitation. The Swedish study, which uses 25 Gy in five fractions per week leads to an increased rate of acute and late toxicities. A fractionation schedule using 45-50 Gy in five weeks should be preferred. During the radiotherapy the patient is followed-up once per week. If surgery is foreseen, it should take place as soon as 3 weeks after the end of radiotherapy. If a primary surgery is performed preoperatively, the operative finding should be discussed with the surgeon. Quality control programs have to certify optimal treatment of the patient by radiotherapist and surgeon.

Rapid growth of microscopic rectal cancer as a determinant of response to preoperative radiation therapy.

PURPOSE: To quantify the dose-time fractionation factors in preoperative radiation therapy for microscopic pelvic deposits of rectal cancer. This provides a biologic basis for understanding and improving the results of adjuvant therapies for this disease. METHODS: The reduction in incidence of pelvic relapses as a function of radiation dose and overall treatment time was determined from the literature. The displacement of dose-response curves to higher doses reflects the growth during radiation treatment of subclinical pelvic deposits which are beyond the future surgical margins. RESULTS: Dose-response curves are steep if the effect of overall duration of radiation therapy is accounted for. The time-related displacement of these steep dose-response curves is consistent with a median doubling time for malignant clonogenic cells of about 4 or 5 days, much faster than the growth rate of the average primary tumor at diagnosis. This rapid growth is evident within the first few days of irradiation, implying that the natural growth rate of these microscopic deposits if fast, and/or that an acceleration of growth follows initiation of radiation injury with a very short lag time. CONCLUSION: Subclinical pelvic deposits of rectal cancer grow rapidly during preoperative radiation therapy with an adverse influence on the rate of pelvic tumor control from protracting the duration of adjuvant treatment. Low doses only offer clinically relevant reduction in risk of pelvic relapses if the overall radiation treatment time is short. For a given overall treatment duration there is a relatively steep dose-response curve, predicting that significant improvements in tumor control are possible.

Simple cyst in the postmenopausal patient: detection and management.

The aims of our study were to determine the prevalence of simple ovarian cysts in asymptomatic postmenopausal patients and to investigate the natural history of these cysts by ultrasonographic follow-up examinations. Three thousand five hundred and eighty-five women participated in the volunteer pelvic cancer screening program. Entry criteria were as follows: postmenopausal, no clinical symptoms, and no previous gynecologic pathology. An anechoic, small cyst less than 5 cm in greatest diameter was classified as a simple ovarian cyst. A scoring system to determine malignant potential had been established previously. All simple cysts had a score of 2 or less and had a morphology typical of benign lesions. In the case of a positive finding, the patient would be seen at 3 to 6 month intervals. The decision for surgical intervention was made by a private gynecologist or patient or if an interval change was noted. One thousand seven hundred and sixty-nine postmenopausal women (49.34% of all patients from the screening program) participated in this study. One hundred and sixteen simple cysts were found, with a prevalence of 6.6% in our population. Among those patients, 27 (23.28%) simple cysts resolved spontaneously, 69 (59.48%) have persisted, and 20 (17.24%) have been lost to follow-up study. Eighteen women (26.09%) with persistent simple ovarian cyst underwent surgery. No malignant ovarian conditions were identified. In conclusion, simple ovarian cysts are more common in postmenopausal women than previously was thought. This condition is very unlikely to be malignant and can be followed conservatively.