Near-infrared photoimmunotherapy (NIR-PIT) of bone metastases.

The bones are a common site for metastasis arising from solid tumors such as breast and prostate cancer. Chemotherapy, including immunotherapy, is rarely curative. Radiotherapy with pain palliation can temporize bone metastases but is generally considered a short-term solution and retreatment is difficult. Surgery is often necessary, yet recovery times might exceed life expectancy. Therefore, there is a need to develop new approaches to bone metastases that are effective but minimally invasive. Near-infrared photoimmunotherapy (NIR-PIT) uses antibodies labeled with IRDye700DX (IR700) which is activated by NIR light, resulting in rapid cell membrane damage and immunogenic cell death. NIR-PIT using an anti-epidermal growth factor receptor (EGFR) antibody-IR700 conjugate in patients with recurrent head and neck cancer received qualified approval in Japan in 2020 and is now widely used there. However, no bone metastases have yet been treated. In this study, the efficacy of NIR-PIT for bone metastases was investigated using a bone metastases mouse model successfully established by caudal artery injection of a human triple-negative breast cancer cell line, MDAMB468-GFP/luc. The bone metastatic lesions were treated with NIR-PIT using the anti-EGFR antibody, panitumumab-IR700 conjugate. Bioluminescence imaging and histological evaluation showed that EGFR-targeted NIR-PIT has a therapeutic effect on bone metastatic lesions in mice. In addition, micro-CT showed that repeated NIR-PIT led to repair of metastasis-induced bone destruction and restored bone cortex continuity consistent with healing. These data suggest that NIR-PIT has the potential for clinical application in the treatment of bone metastases.

Preoperative Chemotherapy for Operable Colon Cancer: Mature Results of an International Randomized Controlled Trial.

PURPOSE: Neoadjuvant chemotherapy (NAC) has potential advantages over standard postoperative chemotherapy for locally advanced colon cancer but requires formal evaluation. METHODS: Patients with radiologically staged T3-4, N0-2, M0 colon cancer were randomly allocated (2:1) to 6 weeks oxaliplatin-fluoropyrimidine preoperatively plus 18 postoperatively (NAC group) or 24 weeks postoperatively (control group). Patients with RAS-wildtype tumors could also be randomly assigned 1:1 to receive panitumumab or not during NAC. The primary end point was residual disease or recurrence within 2 years. Secondary outcomes included surgical morbidity, histopathologic stage, regression grade, completeness of resection, and cause-specific mortality. Log-rank analyses were by intention-to-treat. RESULTS: Of 699 patients allocated to NAC, 674 (96%) started and 606 (87%) completed NAC. In total, 686 of 699 (98.1%) NAC patients and 351 of 354 (99.2%) control patients underwent surgery. Thirty patients (4.3%) allocated to NAC developed obstructive symptoms requiring expedited surgery, but there were fewer serious postoperative complications with NAC than with control. NAC produced marked T and N downstaging and histologic tumor regression (all P < .001). Resection was more often histopathologically complete: 94% (648/686) versus 89% (311/351), P < .001. Fewer NAC than control patients had residual or recurrent disease within 2 years (16.9% [118/699] v 21.5% [76/354]; rate ratio, 0.72 [95% CI, 0.54 to 0.98]; P = .037). Tumor regression correlated strongly with freedom from recurrence. Panitumumab did not enhance the benefit from NAC. Little benefit from NAC was seen in mismatch repair-deficient tumors. CONCLUSION: Six weeks of preoperative oxaliplatin-fluoropyrimidine chemotherapy for operable colon cancer can be delivered safely, without increasing perioperative morbidity. This chemotherapy regimen, when given preoperatively, produces marked histopathologic down-staging, fewer incomplete resections, and better 2-year disease control. Histologic regression after NAC is a strong predictor of lower postoperative recurrence risk so has potential use as a guide for postoperative therapy. Six weeks of NAC should be considered as a treatment option for locally advanced colon cancer.

Acupuncture in the Treatment of Panitumumab Skin Toxicity: A Case Report.

BACKGROUND: Inflammatory skin rash resulting from treatment with epidermal growth factor receptor inhibitors may cause physical and mental disabling to patients treated for their oncologic condition and may, in some cases, lead to the cessation of biological treatment. CASE REPORT: In this case report, acupuncture treatment was provided to a patient with metastatic colorectal carcinoma who developed skin toxicity from panitumumab including rash, itching, and skin inflammation. Itching, infection, and inflammation symptoms improved significantly following acupuncture, subsequently relapsed following treatment cessation, and improved once again following reintroduction of acupuncture. CONCLUSION: Acupuncture may be effective in alleviating panitumumab-related skin inflammatory symptoms.

FOLFOX plus panitumumab or FOLFOX alone as additive therapy following R0/1 resection of RAS wild-type colorectal cancer liver metastases - The PARLIM trial (AIO KRK 0314).

PURPOSE: This trial investigates the addition of panitumumab to chemotherapy with fluorouracil/folinic acid and oxaliplatin (FOLFOX) in a 2:1 randomised, controlled, open-label, phase II trial in RAS wild-type colorectal cancer patients with R0/1-resected liver metastases. EXPERIMENTAL DESIGN: The primary endpoint was progression-free survival (PFS) two years after randomisation. The experimental arm (12 weeks of biweekly mFOLFOX6 plus panitumumab followed by 12 weeks of panitumumab alone) was considered active if the two-year PFS rate was ≥65%. Based on historical data, a two-year PFS rate of 50% was estimated in the control arm (12 weeks of biweekly FOLFOX). The trial was performed with a power of 80% and an alpha of 0.05. Secondary endpoints included overall survival (OS) and toxicity. The trial is registered with ClinicalTrials.gov, NCT01384994. RESULTS: The full analysis set consists of 70 patients (pts) in the experimental arm and 36 pts in the control arm. The primary endpoint was missed with a two-year PFS of 35.7% with FOLFOX plus panitumumab and 30.6% in the control arm. In comparative analyses, trends towards improved PFS (HR 0.83; 95%CI, 0.52-1.33; P = 0.44) and OS (HR 0.70; 95% CI, 0.34-1.46; P = 0.34) were observed in favour of the panitumumab-based study arm. No new or unexpected safety signals were observed with FOLFOX plus panitumumab following liver resection. CONCLUSION: The PARLIM trial failed to demonstrate a two-year PFS rate of 65% after resection of colorectal liver metastases. The positive trends in survival endpoints may support future trials evaluating treatment with anti-EGFR agents after resection of liver metastases.

Hematochezia Due to Panitumumab-induced Colitis with Vitamin K Deficiency.

Panitumumab, a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody, has been shown to be useful in treating either advanced or recurrent KRAS/NRAS/BRAF wild-type colorectal cancer. We herein report the case of a 60-year-old man with short bowel syndrome who developed hematochezia due to panitumumab-induced colitis with vitamin K deficiency during third-line chemotherapy. The cause of vitamin K deficiency was the lack of intravenous vitamin K supplementation following a change from central venous nutrition to peripheral venous nutrition. We advise clinicians to carefully check for colitis and manage the infusions of chemotherapy patients with short bowel syndrome.

A Randomized Phase II Trial of Adjuvant Hepatic Arterial Infusion and Systemic Therapy With or Without Panitumumab After Hepatic Resection of KRAS Wild-type Colorectal Cancer.

OBJECTIVE/BACKGROUND: The purpose was to determine whether adding Pmab versus no Pmab to an adjuvant regimen of hepatic arterial infusion (HAI) of floxuridine (FUDR) plus systemic (SYS) leucovorin, fluorouracil, and irinotecan (FOLFIRI) improves 15-month recurrence-free survival for patients with RAS wild-type colorectal cancer. Secondary endpoints included overall survival, toxicity, and influence of predictive biomarkers. METHODS: This phase II trial randomized patients with KRAS wild-type resected colorectal liver metastases to adjuvant HAI FUDR + SYS FOLFIRI +/- Pmab (NCT01312857). Patients were stratified by clinical risk score and previous chemotherapy. Based on an exact binomial design, if one arm had ≥24 patients alive and disease-free at 15 months that regimen was considered promising for further investigation. RESULTS: Seventy-five patients were randomized. Patient characteristics and toxicity were not different in the 2 arms, except for rash in +Pmab arm. Grade 3/4 elevation in bilirubin or alkaline phosphatase did not differ in the 2 arms. Twenty-five (69%; 95% CI, 53-82) patients in the Pmab arm versus 18 (47%; 95% CI, 32-63) patients in the arm without Pmab were alive and recurrence-free at 15 months. Only the Pmab arm met the decision rule, while the other arm did not. After median follow-up of 56.6 months, 3-year recurrence-free survival was 57% (95% CI, 43-76) and 42% (95% CI, 29-61), and 3-year overall survival was 97% (95% CI, 90-99) and 91% (95% CI, 83-99), +/- Pmab, respectively. CONCLUSIONS: The addition of Pmab to HAI FUDR + SYS FOLFIRI showed promising activity without increased biliary toxicity and should be further investigated in a larger trial.

Effective chemotherapy and targeted therapy supplemented with stereotactic radiotherapy of a patient with metastatic colon cancer following renal transplantation: a case report.

BACKGROUND: Previous studies have shown that patients who underwent renal transplantation were at a greater risk of developing malignancies. Due to advances in effective surgical techniques and immunosuppressive therapies, organ recipients live longer. Yet, there is insufficient information about the recommended type of therapy for colorectal cancer patients following transplantation. We describe the oncological treatment of a patient with renal transplantation, who presented with metastatic colon cancer 5 years after transplantation. CASE PRESENTATION: A 66-year-old Caucasian male patient, with hypertension, type 2 diabetes mellitus, paroxysmal atrial fibrillation, and renal failure underwent successful kidney transplantation in 2013. In April 2018, the adenocarcinoma of the sigmoid colon was found, and surgical resection was performed. The histological diagnosis was low-grade adenocarcinoma. Fluorodeoxyglucose positron emission tomography/computerized tomography scan showed a 2.5-cm metastasis in the VIIth segment of the liver and a metastatic paraaortical lymph node on the left. The clinical diagnosis was, therefore, metastatic (stage IV) sigmoid colon cancer (AJCC TNM system). The ongoing medications of the patient included immunosuppressive drugs and medication for his cardiovascular comorbidities. In July 2018, palliative cetuximab plus folinic acid-fluorouracil-irinotecan chemotherapeutic treatment was initiated, then cetuximab was substituted for panitumumab because of adverse events. In August 2018, the follow-up positron emission tomography/computerized tomography scan revealed stable disease. Because of side effects, the patient was unwilling to continue with the panitumumab plus folinic acid-fluorouracil-irinotecan treatment regimen. Therefore, the patient received 10× 5 Gy stereotactic body irradiation for his liver metastasis and mono-panitumumab therapy. By January 2019, the positron emission tomography/computerized tomography scan showed regression of the liver metastasis but a progression in the paraaortic lymph node. Therefore, 5× 8 Gy stereotactic irradiation was given to the paraaortic lesion. Meanwhile, the patient received altogether 16 cycles of panitumumab until June 2019, when complete remission was attained. In July 2019, the patient suffered a hemorrhagic stroke, probably due to his cardiovascular comorbidities, and died subsequently. CONCLUSIONS: Since information is scarce regarding oncological treatment of patients following organ transplantation, data about their oncological treatment is essential. To our knowledge, this is the first case report to describe the successful chemotherapy and targeted therapy supplemented with stereotactic radiotherapy of a posttransplant patient with metastatic colorectal cancer.

[A Case of Hyperammonemic Encephalopathy following mFOLFOX6 plus Panitumumab Therapy for Rectal Cancer].

An 80-year-old man underwent laparoscopic rectal high anterior resection with perineal dissemination for the management of RS rectal cancer. Following the diagnosis of RS rectal cancer with muc, pT4a, N3(14/15), M1c, P1, pStage Ⅳc, RAS/BRAF: wild type, treatment was initiated with mFOLFOX6 plus panitumumab(Pmab). Laboratory examination on admission revealed mild renal dysfunction(Cr 1.45 mg/dL). The patient became confused on day 3 of chemotherapy(JCS Ⅲ-200). Furthermore, laboratory findings revealed a serum ammonia level of 338µg/dL. He was diagnosed with 5-FU- induced hyperammonemic encephalopathy. Discontinuation of high-dose 5-FU and branched-chain amino acid solutions improved his mental status and decreased serum ammonia levels. We switched his chemotherapy regime to CPT-11 plus Pmab, but it was discontinued after 1 course on his request.

Near-infrared photoimmunotherapy (NIR-PIT) on cholangiocarcinoma using a novel catheter device with light emitting diodes.

Near-infrared photoimmunotherapy (NIR-PIT) is a novel therapy for cancers that uses NIR light and antibody-photosensitizer (IR700) conjugates. However, it is difficult to deliver NIR light into the bile duct for cholangiocarcinoma (CCA) from the conventional extracorporeal apparatus. Thus, in this study, we developed a dedicated catheter with light emitting diodes (LEDs) that supersedes conventional external irradiation devices; we investigated the therapeutic effect of NIR-PIT for CCA using the novel catheter. The new catheter was designed to be placed in the bile duct and a temperature sensor was attached to the tip of the catheter to avoid thermal burn. An anti-epidermal growth factor receptor (EGFR) antibody, Panitumumab-IR700 conjugate or anti-human epidermal growth factor receptor type 2 (HER2) antibody, Trastuzumab-IR700 conjugate, was used with EGFR- or HER2-expressing cell lines, respectively. The in vitro efficacy of NIR-PIT was confirmed in cultured cells; the capability of the new catheter for NIR-PIT was then tested in a mouse tumor model. NIR-PIT via the developed catheter treated CCA xenografts in mice. NIR-PIT had an effect in Panitumumab-IR700 conjugate- and Trastuzumab-IR700 conjugate-treated CCA cells that depended on the receptor expression level. Tumor growth was significantly suppressed in mice treated with NIR-PIT using the novel catheter compared with controls (P < .01). NIR-PIT was an effective treatment for EGFR- and HER2-expressing CCA cells, and the novel catheter with mounted LEDs was useful for NIR-PIT of CCA.

Eficacia y seguridad de panitumumab más folfiri para el tratamiento de pacientes adultos con cáncer colorrectal con gen kras no mutado que recibió terapia adyuvante con esquemas de oxaliplatino sin irinotecán y que progresa a metástasis, con ECOG 0-1 / Efficacy and safety of panitumumab plus folfiri for the treatment of adult patients with kras wild-type colorectal cancer receiving adjuvant therapy with oxaliplatin regimens without irinotecan and progressing to metastases, with ECOG 0-1

INTRODUCCIÓN: El presente dictamen expone la evaluación de la eficacia y seguridad de panitumumab más FOLFIRI, comparado con FOLFIRI solo, para el tratamiento de pacientes adultos con cáncer colorrectal con gen KRAS no mutado (wild type) que recibió terapia adyuvante con esquemas de oxaliplatino sin irinotecán y que progresa a metástasis, con ECOG 0-1. A nivel mundial, el cáncer colorrectal es la cuarto tipo de cáncer más frecuente. En el Perú, es la cuarta causa de muertes por cancer, con alrededor de 2367 muertes y una tasa de incidencia estandarizada por edad de 13.3 por cada 100,000 habitantes, reportados al 2018. Aproximadamente del 20 ­ 25 % se encuentra en fase metastásica al momento del diagnóstico. El objetivo del tratamiento del cáncer colorrectal metastásico (CCRm) es mejorar la calidad de vida y prolongar la sobrevida del paciente. El manejo de los pacientes con CCRm en un buen estado funcional (ECOG 0-1) incluye como primera línea de tratamiento la quimioterapia a base de fluoropirimidinas (5-fluorouracilo y capecitabina), como FOLFOX (5-fluorouracilo + leucovorina + oxaliplatino), CAPOX o XELOX (capecitabina + oxaliplatino), FOLFIRI (5-fluorouracilo + leucovorina + irinotecan), y FOLFIRINOX (5-fluorouracilo + leucovorina + irinotecan + oxaliplatino), todos los cuales se encuentran actualmente disponibles en el Petitorio Farmacológico de EsSalud. Actualmente se han propuesto nuevos tratamientos con productos biológicos basados en anticuerpos monoclonales para la identificación e inhibición del receptor del factor de crecimiento epidérmico (EGFR, por sus siglas en inglés) o el factor de crecimiento del endotelio vascular (VEGF, por sus siglas en ingles). Al respecto, los especialistas señalan que particularmente para un grupo de pacientes con cancer colorrectal, con gen KRAS no mutado, con buen estado funcional (ECOG 0-1), que recibieron terapia adyuvante con esquemas de oxaliplatino sin irinotecán y que progresan a metástasis, la opción de tratamiento para el CCRm, en el contexto de primera línea, es la quimioterapia con FOLFIRI. No obstante, sugieren que la adición de un producto biológico (panitumumab) a la terapia con FOLFIRI podría ser beneficioso para el paciente. Panitumumab es un anticuerpo monoclonal IgG2 humano contra el receptor del factor de crecimiento epidérmico (EGFR). El EGFR juega un rol importante en el desarrollo de CCR, por lo que su inhibición podría dar la impresión de representar una estrategia prometedora para el tratamiento. Panitumumab ha sido aprobada por la agencia europea European Medicines Agency (EMA) y la Dirección General de Medicamentos Insumos y Drogas (DIGEMID) para su uso en combinación con FOLFIRI como primera línea de tratamiento para pacientes adultos con CCRm, con gen KRAS no mutado. No obstante, no ha sido aprobada por la Food and Drug Administration (FDA) para el mismo uso. METODOLOGÍA: Se llevó a cabo una búsqueda bibliográfica con el objetivo de identificar la mejor evidencia disponible sobre la eficacia y seguridad de panitumumab más FOLFIRI, comparado FOLFIRI solo, para el tratamiento de pacientes adultos con CCR con gen KRAS no mutado que recibió terapia adyuvante con esquemas de oxaliplatino sin irinotecán y que progresa a metástasis, con ECOG 0-1. La búsqueda se inició con la revisión de la información sobre el uso del medicamento de acuerdo con entidades reguladoras como FDA, EMA, DIGEMID y la OMS. La búsqueda sistemática se realizó en las principales bases de datos: Medline vía PubMed, The Cochrane Library y LILACS. Asimismo, se realizó una búsqueda manual dentro de las bases de datos pertenecientes a grupos que realizan evaluación de tecnologías sanitarias y guías de práctica clínica (GPC) incluyendo: la National Institute for Health and Care Excellence (NICE), Canadian Agency for Drugs and Technologies in Health (CADTH), Scottish Medicines Consortium (SMC), Scottish Intercollegiate Guidelines Network (SIGN), Institute for Clinical and Economic Review (ICER), The Institute for Quality and Efficiency in Healthcare (IQWiG por sus siglas en alemán), Base regional de informes de evaluación de tecnologías en salud de las Américas (BRISA) la Organización Mundial de la Salud (OMS), el Ministerio de Salud del Perú (MINSA) y el Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI). Además, se realizó una búsqueda de GPC de las principales sociedades o instituciones especializadas en cáncer colorectal, tales como: The National Comprehensive Cancer Network (NCCN), Japanese Society for Cancer of the Colon and Rectum (JSCCR), European Society for Medical Oncology (ESMO) y American Society of Clinical Oncology (ASCO). Finalmente, se realizó una búsqueda en la página web de registro de ensayos clínicos (EC) www.clinicaltrials.gov, para identificar EC en curso o que no hayan sido publicados aún. RESULTADOS: De acuerdo con la pregunta PICO, se llevó a cabo una búsqueda sistemática de evidencia científica relacionada al uso de panitumumab más FOLFIRI como tratamiento de pacientes adultos con CCR, gen KRAS no mutado, que recibió terapia adyuvante con esquemas de oxaliplatino sin irinotecán y que progresa a metástasis, con ECOG 0-1. La presente sinopsis describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad (GPC, ETS, RS con o sin meta análisis y estudios primarios). CONCLUSIONES: El presente dictamen preliminar tuvo por objetivo evaluar la mejor evidencia disponible en torno a la eficacia y seguridad de panitumumab más FOLFIRI comparado FOLFIRI solo para el tratamiento de pacientes adultos con cáncer colorrectal con gen KRAS no mutado (wild type) que recibió terapia adyuvante con esquemas de oxaliplatino sin irinotecán y que progresa a metástasis, con ECOG 0-1. Tras la búsqueda sistemática de la literatura se identificaron cinco GPC (NCCN, NICE, JSCCR, ESMO y SIGN), dos ETS (SMC y NICE) y un ensayo clínico fase II de etiqueta abierta sin grupo de comparación publicado por Köhne et al. 2012. De las cinco GPC evaluadas, solo una recomendó específicamente el esquema de interés, otras dos plantearon recomendaciones generales que incluían al esquemas de interés y las últimas dos, no recomendaron el uso FOLFIRI más panitumumab. La evidencia de soporte utilizadas por las guías que presentaron recomendaciones a favor, fueron distintas y de baja calidad (ensayo clínico fase II o de extrapolaciones de resultados). En línea con ello, el comité de la SMC optó por no recomendar el uso de FOLFIRI más panitumumab, básicamente por falta de evidencia de respaldo. Por otra parte, el comité de NICE, a pesar de reconocer la falta de evidencia, optó por recomendar el esquema de interés, apoyándose en la extrapolación de los resultados de estudios basados en esquemas con FOLFOX y no FOLFIRI. Por otro lado, el ensayo clínico fase II, de etiqueta abierta, sin grupo comparador, mostró una similar SLP y un mayor porcentaje de EA serios (>50% de la población), a la reportada por otros estudios que evaluaron solo FOLFIRI como tratamiento de primera línea en pacientes con CCRm. Y aunque es necesario corroborar estos hallazgos con ECAs fase III que evalúen adecuadamente ambos tratamientos, estos hallazgos parecen mostrar similar eficacia y peor perfil de seguridad para FOLFIRI más panitumumab comparado con FOLFRIRI solo. Tomando en cuenta estos aspectos y que particularmente, que, hasta la fecha, la FDA no ha aprobado el uso de panitumumab en combinación con FOLFIRI como primera línea de tratamiento para pacientes con CCRm, con gen KRAS no mutado. Se concluye que, aunque existe incertidumbre respecto al verdadero balance riego/beneficio del uso de FOLFIRI más panitumumab comparado con FOLFIRI solo en la población de interés para el presente dictamen, las evidencia indirecta mostró mayor riesgo que beneficio sobre el uso de FOLFIRI más panitumumab comparado con el uso de FOLFIRI solo, en la población de interés. Por lo expuesto, el IETSI no aprueba el uso de FOLFIRI más panitumumab para el tratamiento de pacientes adultos con cáncer colorrectal con gen KRAS no mutado (wild type) que recibió terapia adyuvante con esquemas de oxaliplatino sin irinotecán y que progresa a metástasis, con ECOG 0-1.

A prospective, single-arm, multicenter trial of neoadjuvant chemotherapy with mFOLFOX6 plus panitumumab without radiotherapy for locally advanced rectal cancer.

PURPOSE: The present study evaluated the safety and efficacy of neoadjuvant chemotherapy with modified 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus panitumumab in clinical stage III rectal cancer with KRAS wild-type. METHODS: We conducted a prospective multicenter phase II trial. KRAS wild-type clinical stage III rectal cancer patients were enrolled. Patients received 6 cycles of mFOLFOX6 with 6 mg/kg panitumumab as neoadjuvant chemotherapy. The primary outcome was the response rate (RR) defined by RECIST. Lateral lymph node dissection (LLDN) was performed when patients had a locally advanced tumor < 9 cm from the anal margin. RESULTS: A total of 50 patients were enrolled. Twelve (24.0%) experienced grade 3-4 adverse events during neoadjuvant chemotherapy. The RR was 88.0% (complete response 2.0%, partial response 86.0%), which met the primary outcome. All patients underwent laparoscopic surgery and achieved R0 resection. Seven patients underwent resection of other adjacent organs, and 43 underwent LLND. Twelve patients (24.0%) experienced grade 3-4 postoperative complications, and 4 (8.0%) had pathological complete response (pCR). Thirteen patients (26.0%) had lymph node metastasis. Forty-five patients (90.0%) received postoperative adjuvant chemotherapy. The 3-year relapse-free survival (RFS) and overall survival (OS) rates were 79.0% and 93.7%, respectively. CONCLUSIONS: Neoadjuvant chemotherapy of mFOLFOX6 plus panitumumab without radiotherapy resulted in a low pCR rate but a high PR rate, low local recurrence rate, and good long-term outcome, suggesting that this treatment strategy may be a viable option for patients unable or unwilling to receive radiotherapy. The trial was registered with the UMIN Clinical Trials Registry, number 000006039.

The efficacy and safety of panitumumab supplementation for colorectal cancer: A meta-analysis of randomized controlled studies.

BACKGROUND: The efficacy of panitumumab supplementation for colorectal cancer remains controversial. We conduct a systematic review and meta-analysis to explore the influence of panitumumab supplementation on treatment efficacy of colorectal cancer. METHODS: We search PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through June 2019 for randomized controlled trials (RCTs) assessing the efficacy of panitumumab supplementation for colorectal cancer. This meta-analysis is performed using the random-effect model. RESULTS: Five RCTs are included in the meta-analysis. Overall, compared with control group for colorectal cancer, panitumumab supplementation is associated with the increase in objective response for wild-type (WT) KRAS (RR = 1.70; 95% CI = 1.07-2.69; P = .03), but has no remarkable influence on objective response for mutant KRAS (RR = 0.92; 95% CI = 0.79-1.08; P = .32), objective response (RR = 1.35; 95% CI = 1.00-1.83; P = 0.05), progressive disease for WT KRAS (RR = 0.94; 95% CI = 0.85-1.02; P = .15), mortality (RR = 0.86; 95% CI = 0.69-1.08; P = .20), or mortality for WT KRAS (RR = 0.94; 95% CI = 0.84-1.05; P = .28). In addition, grade 3 and 4 adverse events are found to be higher in panitumumab group than those in control group (RR = 1.17; 95% CI = 1.08-1.27; P = .0001; ). CONCLUSIONS: Panitumumab supplementation can provide some improvement in objective response for colorectal cancer patients with WT KRAS, but results in the increase in grade 3 and 4 adverse events.

VITAL phase 2 study: Upfront 5-fluorouracil, mitomycin-C, panitumumab and radiotherapy treatment in nonmetastatic squamous cell carcinomas of the anal canal (GEMCAD 09-02).

AIM: VITAL, a phase II single-arm study, aimed to evaluate efficacy and safety of panitumumab addition to 5-fluorouracil (5-FU), mitomycin-C (MMC) and radiotherapy (RT) in patients with localized squamous cell carcinoma of the anal canal (SCCAC). METHODS: Adult, treatment-naïve SCCAC patients (Stage T2-T4, any N, M0) and ECOG-PS ≤2, received panitumumab (6 mg/kg, day 1 and Q2W; 8 weeks), 5-FU (1000 mg/m2 /d, days 1-4 and 29-32), MMC (10 mg/m2 , days 1 and 29) and RT 45 Gy (1.8 Gy/fraction) to the primary tumor and mesorectal, iliac and inguinal lymph nodes, plus 10-15 Gy boost dose to the primary tumor and affected lymph nodes. The primary objective was disease free survival rate (DFS) at 3-years (expected 3-year DFS rate: 73.7 ± 12%). RESULTS: Fifty-eight patients (31 women; median age: 59 years; ECOG-PS 0-1:98%; TNM II [29%] (T2 or T3/N0/M0)/IIIA (T1-T3/N1/M0 or T4/N0/M0) [21%]/IIIB (T4/N1/M0 or any T/N2 or N3/M0) [47%]/nonevaluable [4%]) were included. The median follow-up was 45 months. The 3-year DFS rate was 61.1% (95% CI: 47.1, 72.4). The 3-year overall survival rate was 78.4% (95% CI: 65.1, 87.1). Eighteen patients (31.0%) required a colostomy within 2 years posttreatment. Grade 3-4 toxicities were experienced by 53 (91%) patients. Most common grade 3-4 treatment-related events were radiation skin injury (40%) and neutropenia (24%). No toxic deaths occurred. Improved efficacy in colostomy-free survival and complete response rate was observed in human papilloma virus positive patients. CONCLUSIONS: Panitumumab addition to MMC-5FU regimen in SCCAC patients increases toxicity and does not improve patients' outcomes. RT plus MMC-5FU remains the standard of care for localized SCCAC patients.

The Pharmacoeconomic Analysis of Cetuximab and Panitumumab in the 1st Line Treatment of mCRC in Real Clinical Practice in the Czech Republic.

BACKGROUND: The anti-epidermal growth factor receptor (EGFR) drugs cetuximab and panitumumab are currently reimbursed when administered during the first and subsequent lines of treatment of patients in the Czech Republic with metastatic colorectal cancer (mCRC). Because cetuximab and panitumumab do not show significant differences in efficacy, their choice may be dependent on cost. This retrospective study analyzed the costs of first-line treatment with cetuximab and panitumumab of patients with mCRC and wild type KRAS, as well as evaluated the correlations between costs and effectiveness, as determined by progression-free survival (PFS) and overall survival (OS). PATIENTS AND METHODS: This analysis included 51 patients with mCRC and confirmed wild type KRAS treated at the comprehensive cancer centre in the Czech Republic between November 2011 and April 2018. Of these 51 patients, 22 were treated with cetuximab and 29 with panitumumab. Direct medical costs (medications, clinical examinations and procedures, and hospitalization) were evaluated from the initiation of treatment with anti-EGFR drug to disease progression and death. Mean follow-up was 21 months in the cetuximab group and 19 months in the panitumumab group. RESULTS: Reimbursement for anti-EGFR drugs until disease progression accounted for 71% (mean, 964,288 CZK per patient) of total costs in the cetuximab group and 77% (mean, 1,003,229 CZK per patient) of total costs in the panitumumab group, with median PFS in these two groups being 10.7 months and 8.1 months, respectively. Reimbursement of expensive center drugs from the start of anti-EGFR treatment to patient death accounted for 55% of total costs in the cetuximab group (mean, 1,752,702 CZK per patient) and 63% of total costs in the panitumumab group (mean, 1,596,919 CZK per patient), with median OS in these two groups being 20.2 months and 19.8 months, respectively. No significant between-group differences in clinical effectiveness and costs of treatment were observed (p > 0.05 each). CONCLUSION: Reimbursement for biological agents is the most expensive item in the first-line treatment of mCRC patients with wild type KRAS, both to disease progression and death. The clinical effectiveness and costs of cetuximab and panitumumab did not differ significantly. Supported by CZECRIN (identification code LM2015090); CZECRIN_4 PACIENTY (No. CZ.02.1.01/0.0/0.0/16_013/0001826). The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 30. 4. 2019 Accepted: 17. 6. 2019.

Epidermal growth factor receptor inhibitor-induced hypomagnesemia: a survey of practice patterns among Canadian gastrointestinal medical oncologists.

Background: The optimal management of hypomagnesemia (hMg) induced by epidermal growth factor receptor inhibitors (egfris) for advanced colorectal cancer is unclear. We surveyed gastrointestinal medical oncologists in Canada to determine practice patterns for the management of egfri-induced hMg. Methods: Based on distribution lists from the Eastern Canadian Colorectal Cancer Consensus Conference and the Western Canadian Gastrointestinal Cancer Consensus Conference, medical oncologists were invited to participate in an online questionnaire between November 2013 and February 2014. Results: From the 104 eligible physicians, 40 responses were obtained (38.5%). Panitumumab was more commonly prescribed than cetuximab by 70% of respondents, with 25% prescribing cetuximab and panitumumab equally. Most respondents obtain a serum magnesium level before initiating a patient on an egfri (92.5%) and before every treatment (90%). Most use a reactive strategy for magnesium supplementation (90%) and, when using supplementation, favour intravenous (iv) alone (40%) or iv and oral (45%) dosing. Magnesium sulfate was used for iv replacement, and the most common oral strategies were magnesium oxide (36.4%) and magnesium rougier (18.2%). Under the reactive strategy, intervention occurred at hMg grade 1 (70.3%) or grade 2 (27%). Of the survey respondents, 45% felt that 1-5 of their patients have ever developed symptoms attributable to hMg, and 35% have had to interrupt egfri therapy because of this toxicity, most commonly at grade 3 (30%) or grade 4 (45%) hMg. The most important question about egfri-induced hMg was its relevance to clinical outcomes (45%) and its symptoms (37.5%). Conclusions: In Canada, various strategies are used in the management of egfri-induced hMg, including prophylactic and reactive approaches that incorporate iv, oral, or a combination of iv and oral supplementation. Clinicians are concerned about the effect of hMg on clinical outcomes and about the symptoms that patients experience as a result of this toxicity.

Targeting Epidermal Growth Factor Receptor (EGFR) and Human Epidermal Growth Factor Receptor 2 (HER2) Expressing Bladder Cancer Using Combination Photoimmunotherapy (PIT).

Bladder cancer (BC) is heterogeneous and expresses various cell surface targets. Photoimmunotherapy (PIT) involves monoclonal antibodies (MAbs) conjugated to a photoabsorber (PA), IR Dye 700Dx, and then activated by near infra-red light (NIR) to specifically target tumors. We have demonstrated that tumors expressing EGFR can be targeted with PIT. However, PIT may be less effective when a tumor lacks "overwhelming" expression of a single target such as EGFR. We present a combinatorial PIT approach for targeting BC expressing EGFR and HER2, using PA- labeled panitumumab (pan) and trastuzumab (tra), respectively. Human BC tissues and cell lines were analyzed for EGFR and HER2 expression. Efficacy of PA-labeled MAbs singly and in combination was analyzed. About 45% of BC tissues stain for both EGFR and HER2. In vitro, the combination of pan IR700 and tra IR700 with NIR was more efficacious than either agent alone. Tumor xenografts treated with combination PIT showed significant tumor growth retardation. Combination PIT is a promising approach for treating BC with low/moderate expression of surface receptors. In addition, given the molecular heterogeneity of bladder cancer, targeting more than one surface receptor may allow for more effective cell death across different bladder tumors.

Influence of oral magnesium-containing supplement and antacid administration on hypomagnesemia induced by panitumumab.

PURPOSE: Hypomagnesemia is a common side effect of panitumumab. The effect of magnesium-containing supplement as a laxative and concomitant antacid (proton pump inhibitor and histamine H2 antagonist) administration on panitumumab-induced hypomagnesemia was retrospectively investigated. METHODS: Patients with advanced or recurrent colorectal cancer who received panitumumab were included in this study. Serum magnesium levels were extracted from the electronic medical records of 1753 administrations in 221 patients who received panitumumab. Serum magnesium levels in patients with or without oral magnesium-containing supplement and antacid treatment were compared using analysis of covariance as the number of panitumumab administration up to 16 times for covariates. RESULTS: The mean serum magnesium levels were significantly decreased with increasing number of panitumumab administrations (2.13 mg/dL at 1st vs. 1.55 mg/dL at 16th, p < 0.001). The use of oral magnesium-containing supplement significantly inhibited the decline in mean serum magnesium level (1.98 mg/dL vs. 1.78 mg/dL, p < 0.001). However, antacid use in patients receiving oral magnesium-containing supplement significantly decreased the effectiveness of the magnesium supplement on serum magnesium level (2.02 mg/dL vs. 1.93 mg/dL, p < 0.05). CONCLUSION: The use of oral magnesium-containing supplement might function as magnesium supplement based on the finding that use of oral magnesium-containing supplement during panitumumab administration decreased hypomagnesemia. However, combination of antacid decreased the supplemental effect of oral magnesium on hypomagnesemia. These results suggest the possibility that use of antacids during anti-EGFR antibody administration may promote hypomagnesemia.

Prognostic Impact of R0 Resection and Targeted Therapy for Colorectal Cancer with Synchronous Peritoneal Metastasis.

BACKGROUND: The National Comprehensive Cancer Network guidelines recommend R0 resection and targeted therapy, a combination of cytotoxic and molecular targeted agents, such as bevacizumab, cetuximab, and panitumumab, for colorectal cancer with synchronous peritoneal metastasis (M1c). While these therapeutic strategies are drawing attention, their efficacy has not been fully examined. METHODS: The study population comprised 248 consecutive M1c patients who were treated at the National Cancer Center Hospital from 1997 to 2013. Multivariate analyses were performed to evaluate relationships between overall survival and R0 resection and targeted therapy using Cox proportional hazards regression models. RESULTS: The 3-year overall survival (3 yOS) was 19.5%, and median survival time (MST) was 16.2 months in 248 M1c patients. R0 resection was performed in 34 patients (14%), yielding a 3-year overall survival (OS) of 48.3% and median survival time (MST) of 29.9 months. Targeted therapy was performed in 54 patients (22%) at least once during the course of treatment, yielding a 3-yr OS of 38.2% and MST of 23.9 months. After adjusting for other key clinical factors, such as the number of organs involved with metastases, performance status, primary tumor site, and extent of peritoneal metastasis, both R0 resection and targeted therapy were independent factors associated with longer OS. Targeted therapy was associated with a significantly longer OS compared with multiple cytotoxic agent therapy [hazard ratio 0.65; 95% confidence interval (0.44-0.94); p = 0.02]. CONCLUSIONS: If achievable, R0 resection is a desirable therapeutic strategy for patients with M1c colorectal cancer. Moreover, targeted therapy might be the optimal chemotherapy in this patient population.

FOLFOX plus anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) is an effective first-line treatment for patients with RAS-wild left-sided metastatic colorectal cancer: A meta-analysis.

BACKGROUND: The efficacy of oxaliplatin-based chemotherapy combined with anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) remains controversial in metastatic colorectal cancer (mCRC). This meta-analysis aims to estimate the effect of adding panitumumab or cetuximab to oxaliplatin-based chemotherapy in RAS wild type mCRC patients for the first-line treatment. The primary tumor location is also considered into this meta-analysis. METHODS: RCT studies were identified by a search of MEDLINE, EMBASE, Cochrane library to October 2017, supplemented by manually retrieving ASCO, ESMO conference abstracts. The pooled hazard ratio (HR) for progression-free survival (PFS) and overall survival (OS), and pooled odds ratios (OR) for the overall response rate (ORR) were calculated by Review Manager 5.3. RESULTS: The results indicated that the addition of anti-EGFR mAbs to FOLFOX regimen in RAS wild-type mCRC patients for the first-line treatment resulted in considerable improvements in PFS (HR = 0.70; 95% confidence interval [CI]: 0.59-0.82; P < .0001), OS (HR = 0.79; 95%CI: 0.67-0.92; P = .003), and ORR (OR = 2.56; 95% CI: 1.77-3.70; P < .00001) compared with chemotherapy alone. However, in RAS/BRAF wild patients, no significant differences were observed when anti-EGFR mAb was added to FLOX or XELOX regimen compared with chemotherapy alone with regard to OS and PFS, whereas FOLFOX+anti-EGFR mAb showed a marked superior OS and PFS (OS, HR = 0.77; 95% CI: 0.61-0.98; P = .03; PFS, HR = 0.68; 95% CI: 0.57-0.82; P < .00001). A meta-analysis including TAILOR and PRIME study suggests that primary tumor location (PTL) predicted a survival benefit when adding the EGFR antibody to FOLFOX regimen in RAS-wild mCRC patients (OS, HR for left-sided: 0.71; 95% CI: 0.59-0.85; P = .0002 and HR for right-sided: 0.90; 95% CI: 0.65-1.25; P = .53). However, the HR for PFS and ORR still suggests a benefit from the addition of anti-EGFR mAb in right-sided mCRC patients. CONCLUSION: So these results suggest anti-EGFR mAb and oxaliplatin are good partners in the FOLFOX regimen. The addition of EGFR antibody to FOLFOX markedly improved efficacy in RAS-wild patients with left-sided mCRC. In RAS/BRAF-wild patients, the efficacy is similar. For patients with right-sided tumor, a benefit showing a trendency in favor of anti-EGFR mAb can still seen. The molecular characteristics behind the tumor location need to be more explored urgently.

Near Infrared Photoimmunotherapy with Combined Exposure of External and Interstitial Light Sources.

Near infrared photoimmunotherapy (NIR-PIT) is a new target-cell-specific cancer treatment that induces highly selective necrotic/immunogenic cell death after systemic administration of a photoabsorber antibody conjugate and subsequent NIR light exposure. However, the depth of NIR light penetration in tissue (approximately 2 cm) with external light sources limits the therapeutic effects of NIR-PIT. Interstitial light exposure using cylindrical diffusing optical fibers can overcome this limitation. The purpose in this study was to compare three NIR light delivery methods for treating tumors with NIR-PIT using a NIR laser system at an identical light energy; external exposure alone, interstitial exposure alone, and the combination. Panitumumab conjugated with the photoabsorber IRDye-700DX (pan-IR700) was intravenously administered to mice with A431-luc xenografts which are epithelial growth factor receptor (EGFR) positive. One and 2 days later, NIR light was administered to the tumors using one of three methods. Interstitial exposure alone and in combination with external sources showed the greatest decrease in bioluminescence signal intensity. Additionally, the combination of external and interstitial NIR light exposure showed significantly greater tumor size reduction and prolonged survival after NIR-PIT compared to external exposure alone. This result suggested that the combination of external and interstitial NIR light exposure was more effective than externally applied light alone. Although external exposure is the least invasive means of delivering light, the combination of external and interstitial exposures produces superior therapeutic efficacy in tumors greater than 2 cm in depth from the tissue surface.