Experimental research of pulmonary injury on irradiation combined with pemetrexed

Objective:The aim of our study was to examine whether irradiation combined with pemetrexed can exacerbate pulmonary injury. Methods:Two groups of male Wister Rats were subjected to bilateral apex of lungs irradiation (a single dose of 12 Gy), with or without pemetrexed (20 mg/kg) by intraperitoneal injection at the same time;a third group of weight-and age-matched animals were treated with pemetrexed alone, as the same dose scheme, time and root of injection. The fourth group served as control. The whole lung mounts were dissected to histological evaluation, while serum cytokine trans-forming growth factor-β1 (TGF-β1) analysis were compared at 1, 7, 21, 35, 49 days post-irradiation after irradiation. Results:Histological examination showed a thickening of alveolar septal, accumulation of inflammatory cells. The irradiation treatment group and the radiation-chemo treatment group showed a statistical y significant higher level of TGF-β1 (P<0.05) than other two groups, but there were no dif erences between these two irradiation groups. Conclusion:These results demonstrated that pemetrexed can not aggravate pulmonary injury and it could be safely used in concurrent or sequential radio-chemo-therapy in lung adenocarcinoma.     

抗肿瘤新药pemetrexed治疗乳腺癌的研究

pemetrexed是一种新型抗叶酸药,能够抑制叶酸代谢途径中的多种酶,从而抑制嘧啶和嘌呤生物的合成,达到抑制肿瘤的作用.Ⅱ期临床结果显示,pemetrexed单药对于初治和复治的进展期乳腺癌均有较高的疗效.毒副作用主要为中性粒细胞减少、食欲减退、乏力和皮疹.补充叶酸和Vit B12可显著减少pemetrexed的血液学毒性,预防性给予皮质激素可减轻皮疹的发生.     

Could hyperthermia with proton therapy mimic carbon ion therapy? Exploring a thermo-radiobiological rationale

Hyperthermia has been conventionally used in conjunction with photon beam irradiation. With a gradual increase in particle therapy facilities worldwide, this paper explores the physical, thermal and radiobiological implications of using a combination of hyperthermia with proton beam therapy. Hyperthermia is known to exhibit radiobiological features similar to those of high linear energy transfer radiation. Protons have many of the physical dose distribution properties of ¹²C ion therapy. Thus, the thermo-radiobiological advantages of hyperthermia coupled with the physical dose distribution advantages of proton beams could possibly mimic ¹²C ion therapy.     

Can docetaxel therapy improve overall survival from primary therapy compared with androgen-deprivation therapy alone in Japanese patients with castration-resistant prostate cancer? A multi-institutional cooperative study

Background

To verify the actual clinical benefit of docetaxel (DOC) therapy and to explore the prognostic factors that may predict overall survival in Japanese patients with castration-resistant prostate cancer (CRPC).

Methods

Baseline characteristics-matched CRPC patients who received conventional androgen-deprivation therapy (ADT) or ADT plus DOC were compared retrospectively. The primary endpoint was overall survival (OS) from primary therapy. Secondary endpoints were response of tumor(s), prostate-specific antigen (PSA) levels, and toxicity.

Results

Median OS was significantly longer in the DOC group (n = 117) than the control group (n = 118) (94.0 vs. 70.0 months, P = 0.0077) and the corresponding hazard ratio (HR) for death in DOC group was 0.566 [95% confidence interval (95%CI) 0.370–0.867; P = 0.0088]. Effective DOC groups [medium dose (50–69 mg/m²) and high dose (≥70 mg/m²)] had significantly longer median OS than control even when survival times were calculated from the start of castration-resistant events (151 vs. 36 months; P = 0.0173) and the corresponding HR for death in the DOC group was 0.515 (95%CI 0.293–0.903; P = 0.0205). In multivariate analysis, statistically significant prognostic indicators were Gleason score, time to CRPC events, and receipt of DOC therapy. Response rate of both measurable lesion and PSA was not significantly different between each DOC dose group. Grade 3 or 4 adverse events associated with low- [30–49 mg/m²], medium-, and high-dose DOC were 21.9, 35.7, and 90.7%, respectively. No death due to DOC therapy was reported.

Conclusion

Treatment with DOC improves OS from primary therapy compared with conventional ADT alone in Japanese patients with CRPC.     

Do antioxidants interfere with radiation therapy for cancer?

Despite recent comprehensive review articles concluding that supplemental antioxidants do not undermine the effectiveness of cytotoxic therapies, the use of antioxidants during cancer treatment remains controversial. Many oncologists take the position that antioxidants by their nature undermine the free radical mechanism of chemotherapy and radiotherapy and should therefore generally be avoided during treatment. For their part, many integrative practitioners believe that antioxidants taken during cancer treatment not only alleviate some of the adverse effects of that treatment but also enhance the efficacy of cancer therapy. Until recently, research attention has focused primarily on the interaction of antioxidants with chemotherapy; relatively little attention has been paid to the interaction of antioxidants with radiotherapy. This article reviews the clinical literature that has addressed whether antioxidants do in fact interfere with radiation therapy. Studies have variously investigated the use of alpha-tocopherol for the amelioration of radiation-induced mucositis; pentoxifylline and vitamin E to correct the adverse effects of radiotherapy; melatonin alongside radiotherapy in the treatment of brain cancer; retinol palmitate as a treatment for radiation-induced proctopathy; a combination of antioxidants (and other naturopathic treatments) and external beam radiation therapy as definitive treatment for prostate cancer; and the use of synthetic antioxidants, amifostine, dexrazoxane, and mesna as radioprotectants. With few exceptions, most of the studies draw positive conclusions about the interaction of antioxidants and radiotherapy. Although further studies are needed, the preponderance of evidence supports a provisional conclusion that dietary antioxidants do not conflict with the use of radiotherapy in the treatment of a wide variety of cancers and may significantly mitigate the adverse effects of that treatment.     

Fibrolamellar hepatocellular carcinoma – Prolonged survival with multimodality therapy

Aim

We report the clinical outcome for a series of ten patients with fibrolamellar hepatocellular treated with resection followed by close surveillance and aggressive management of relapse.

Methods

The case notes for all patients treated at this institution since 1982 were reviewed and details of initial stage and management were extracted along with investigations and treatment of relapse. Time to relapse, overall survival and post-relapse survival were analysed.

Results

Relapse occurred in all ten cases at a median of 2.2 (95% CI 0.9–2.7) years but, with a combination of re-resection, systemic chemotherapy and radiotherapy, the overall median survival was 9.3 (95% CI 3.0–18.5) years. One patient was disease free eight years after two resections for recurrent disease. Two of nine patients had a partial response to cisplatin and fluorouracil while three had stable disease. FDG-PET was positive for recurrence in three of four cases of relapse, and in one case detected recurrence in advance of CT.

Conclusion

The early detection of relapse combined with multimodality therapy results in prolonged survival. Further improvements in systemic therapy are required to improve the prognosis in this disease.     

Phase II study of pemetrexed in combination with cisplatin in patients with advanced urothelial cancer: the PECULIAR study (KCSG 10–17)

Background:

Pemetrexed has shown a favourable response rate of about 30% with minimal toxicity when used as a single agent for treatment of advanced urothelial carcinoma. This phase II study evaluated the efficacy and safety of pemetrexed plus cisplatin in advanced urothelial carcinoma.

Methods:

This multicentre, single-arm, open-label, phase II clinical trial enrolled patients who had advanced urothelial carcinoma, ECOG PS 0–2, and measurable disease. Pemetrexed 500 mg m⁻² with cisplatin 70 mg m⁻² on day 1 were administered every 3 weeks. The primary endpoint was the objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity.

Results:

A total of 42 patients were enrolled (median age, 66 years; ECOG 0–1, 100% visceral metastasis, 54.8% recurrent disease, 57.1%). Twenty-seven partial responses for an ORR of 64.3% (95% CI, 49.2%–77.0%) were documented. Seven patients had stable disease. Median PFS and OS were 6.9 (95% CI, 6.2–7.6) and 14.4 (95% CI, 10.4–18.4) months, respectively. Grade 3 or 4 neutropenia was observed in 28.6% of patients. No patients experienced febrile neutropenia.

Conclusion:

The combination of pemetrexed and cisplatin is active, and well tolerated in patients with advanced urothelial cancer as a first-line treatment.     

Where next with preoperative radiation therapy for rectal cancer?

PURPOSE: The basic question for radiation oncologists is what we hope to achieve from treatments that are adjuvant to surgery: better local (pelvic) control and, hopefully, because of that, fewer metastases. Chemotherapy could add to the local effect of irradiation and may also decrease distant metastases directly. Selection criteria for individual treatment could enhance the therapeutic index. LOCAL CONTROL: Total mesorectal excision reduces the incidence of local recurrence, but preoperative (chemo) radiation is still indicated for more advanced tumors (T3-T4) and for lymph node involvement. Pelvic recurrences arise from tumor clonogens residual beyond the surgical margins. Thus, the practice of shrinking fields to boost the dose to the primary tumor makes no sense, except for tumors that invade residual structures, such as the sacrum. Subclinical disease beyond the future surgical margins grows more quickly than the primary tumor, and hence treatment should be as intense as tolerable. A short treatment course (e.g. 5 x 5 Gy) is desirable, but this regimen, which is currently the gold standard, should be compared (as in the recently closed randomized Polish trial) with higher-dose, longer-duration chemoradiotherapy regimens. The recently closed EORTC trial 22921 examines the benefit of pre- and postoperative chemotherapy combined with a long schedule of radiation. Likewise, continuous infusion of a cycle-active agent rather than bolus administration is a logical addition to radiation therapy in the treatment of fast-growing subclinical tumor extensions. SYSTEMIC DISEASE: The reduction in distant metastasis rates attributable to adjuvant chemotherapy varies greatly among reports. If the reduction is of the order of 10-25%, the efficacy of chemotherapy equates to as little as about 5 to 12.5 Gy and not more than 20 Gy of total body irradiation. INTERVAL BETWEEN RADIATION THERAPY AND POSTRADIATION SURGERY: Early excision after preoperative irradiation would be desirable if the primary tumor were still disseminating viable metastatic clonogens. Most tumors do not metastasize until they contain enough viable clonogens to render them clinically detectable. A dose of 10 Gy in 2 Gy fractions reduces at least 30-fold the absolute number of viable clonogens in the primary tumor, to levels that do not yield metastases from the untreated tumor. After a dose of 44-50 Gy in 2 Gy fractions, there is little chance that the surviving tumor clonogens could regrow to a metastasis-yielding volume in any reasonable radiation-surgery interval. Thus there is no tumor-related necessity for early postradiation surgery. The importance of the interval between radiation and surgery is currently being addressed in a Swedish randomized trial. PROGNOSTIC AND PREDICTIVE CHARACTERIZATION: Tumor volume should be included in the staging system. There are many tumor- and host-related characteristics that can be used to fingerprint the tumor to help select appropriate individual treatment.     

5‐HT3 antiemetic therapy for patients with breast cancer

Antiemetic treatment should be considered for breast cancer patients receiving moderately emetogenic chemotherapy. Although the extent of chemotherapyinduced emesis is largely dependent on the emetogenic potential of the specific agents employed, patient characteristics such as age and sex also contribute. Recent clinical studies show that treatment with the currently available 5HT₃ antagonists effectively reduces the incidence of chemotherapyinduced nausea and vomiting and improves quality of life in a substantial number of these patients.A Medline search from 1994 through February 1998 identified clinical trials that included previously untreated breast cancer patients using antiemetic therapy such as granisetron, ondansetron, dolasetron, and metoclopramide.The studies reviewed here indicate that the antiemetic efficacy of 5HT₃ antagonists is equivalent in previously untreated patients receiving moderately emetogenic chemotherapy for breast cancer, depending on the doses and schedules utilized. In particular, two comparative studies of granisetron and ondansetron with specific data for breast cancer patients showed that both agents eliminate nausea in approximately 50%, and vomiting in 60–70% of these patients, with the higher values observed when steroids were added to the 5HT₃ receptor antagonist regimen.Although the chemotherapy regimens employed for breast cancer are considered only moderately emetogenic, these regimens account for 60–90% of patients experiencing nausea and vomiting. The most recent clinical studies demonstrate that 5HT₃ antagonists can significantly reduce the incidence of nausea in breast cancer patients receiving moderately emetogenic chemotherapy and should be employed in this setting.     

Could conventionally fractionated radiation therapy coupled with stereotactic body radiation therapy improve local control in bone oligometastases?

PurposeTo describe clinical outcomes of stereotactic body radiation therapy (SBRT) applied alone or as a boost after a conventionally fractionated radiation therapy (CFRT) for the treatment of bone oligometastases.Material and MethodsThis retrospective cohort study included patients treated with SBRT from January 2007 to December 2015 in the Institut de cancérologie de Lorraine in France. The inclusion criteria involved adults treated with SBRT for one to three bone metastases from a histological proven solid tumor and a primary tumor treated, an Eastern Cooperative Oncology Group (ECOG) score inferior or equal to 2. Local control (LC), overall survival (OS), progression free survival (PFS), bone progression incidence (BPI), skeletal related events free survival (SRE-FS), toxicity and pain response were evaluated.ResultsForty-six patients and 52 bone metastases were treated. Twenty-three metastases (44.2%) received SBRT alone mainly for non-spine metastases and 29 (55.8%) a combination of CFRT and SBRT mainly for spine metastases. The median follow-up time was 22 months (range: 4–89 months). Five local failures (9.6%) were observed and the cumulative incidences of local recurrence at 1 and 2 years respectively were 4.4% and 8% with a median time of local recurrence of 17 months (range: 4–36 months). The one- and two-years OS were 90.8% and 87.4%. Visceral metastasis (HR: 3.40, 95% confidence interval [1.10–10.50]) and a time from primary diagnosis (TPD) > 30 months (HR: 0.22 [0.06–0.82]) were independent prognostic factors of OS. The 1 and 2 years PFS were 66.8% and 30.9% with a median PFS time of 18 months [13–24]. The one- and two-years BPI were 27.7% and 55.3%. In multivariate analysis, unfavorable histology was associated with worse BPI (HR: 3.19 [1.32–7.76]). The SRE-FS was 93.3% and 78.5% % at 1 and 2 years. The overall response rate for pain was 75% in the evaluable patients (9/12). No grade ≥ 3 toxicity nor especially no radiation induced myelopathy (RIM), two patients developed asymptomatic vertebral compression fractures.ConclusionThe sole use of SBRT or its association with CFRT is an efficient and well-tolerated treatment that allows high LC for bone oligometastases.