Actionable tests and treatments for patients with gastrointestinal cancers and historically short median survival times.

BACKGROUND: Patients have difficult unmet needs when standard chemotherapy produces a median survival of less than 1 year or many patients will experience severe toxicities. Blood tests can predict their survival. METHODS: Analyses evaluate predictive blood tests to identify patients who often survive 1 and 2 years. A four-test model includes: albumin, absolute neutrophil count, neutrophil-lymphocyte ratio, and lymphocyte-monocyte ratio. Individual tests include: alkaline phosphatase, lymphocytes, white blood count, platelet count, and hemoglobin. Eligible patients have advanced: resistant 3rd line colorectal, and both resistant and new pancreatic and intrahepatic bile duct cancers. Eligibility characteristics include: biopsy-proven, measurable metastatic disease, NCI grade 0-2 blood tests, Karnofsky Score 100-50, and any adult age. Drugs are given at 1/4-1/3 of their standard dosages biweekly: gemcitabine, irinotecan, fluorouracil, leucovorin, and day 2 oxaliplatin every 2 weeks. In case of progression, Docetaxel is added (except colon cancer), with or without Mitomycin C, and next cetuximab (except pancreatic and KRAS BRAF mutation cancers). Bevacizumab is substituted for cetuximab in case of another progression or ineligibility. Consent was written and conforms with Helsinki, IRB, and FDA criteria (FDA #119005). RESULTS: Median survival is 14.5 months. Of 205 patients, 60% survive 12, and 37% survive 24 months (95% CI ± 8%). Survival is > 24, 13, and 3.8 months for patients with 0, 1-2, and 3-4 unfavorable tests, respectively. Individual "favorable and unfavorable" tests predict long and short survival. Neither age nor prior therapy discernibly affects survival. Net rates of clinically significant toxicities are less than 5%. CONCLUSION: Treatments reproduce predictable, greater than 12 and 24-month chances of survival for the aged and for patients with drug-resistant tumors. Evaluation of blood tests may change practice, expand eligibility, and personalize treatments. Findings support investigation of drug combinations and novel dosages to reverse resistance and improve safety.

Tumor protein p53 mutation in archived tumor samples from a 12-year survivor of stage 4 pancreatic ductal adenocarcinoma may predict long-term survival with DeltaRex-G: A case report and literature review.

DeltaRex-G is a replication-incompetent amphotropic murine leukemia virus-based retroviral vector that displays a collagen-matrix-targeting decapeptide on its surface envelope protein, gp70, and encodes a cytocidal 'dominant negative', i.e. a truncated construct of the executive cyclin G1 (CCNG1) oncogene. DeltaRex-G inhibits the CCNG1 function of promoting cell competence and survival through the commanding CCNG1/cyclin-dependent kinase (CDK)/Myc/mouse double minute 2 homolog (Mdm2)/p53 axis. In 2009, DeltaRex-G was granted Fast Track designation from the US Food and Drug Administration for the treatment of pancreatic cancer. In 2019, the results of a phase 1/2 study that used DeltaRex-G as monotherapy for stage 4 chemotherapy-resistant pancreatic ductal adenocarcinoma (PDAC) were published. A unique participant of the aforementioned phase 1/2 study is now an 84-year-old Caucasian woman with chemoresistant PDAC who was treated with DeltaRex-G, 3x1011 colony forming units (cfu)/dose, 3 times/week for 4 weeks with a 2-week rest period, for 1.5 years. During the treatment period, the patient's tumors in the liver, lymph node and peritoneum exhibited progressive decreases in size, which were accompanied by a reduction and normalization of serum carbohydrate antigen 19-9 levels, and the patient achieved complete remission after 8 months of DeltaRex-G therapy with minimal side effects (grade 2 fatigue). Henceforth, the patient has been in remission for 12 years with no evidence of disease, no late therapy-related adverse events, and no further cancer therapy following DeltaRex-G treatment. The present study reports a mutation of tumor protein p53 (TP53) (G199V) found retrospectively in the patient's archived tumor samples. TP53 is a well-characterized tumor suppressor gene, and a critical regulatory component of the executive CCNG1/CDK/Myc/Mdm2/p53 axis, which regulates proliferative cell competence, DNA fidelity and survival. Studies are underway to determine whether TP53 mutations in pancreatic cancer can help identify a subset of patients with advanced metastatic cancer with an otherwise poor prognosis who would respond favorably to DeltaRex-G, which would broaden the treatment options for patients with otherwise lethal PDAC.

Ileal Adenocarcinoma with Liver Metastasis in Patient with Crohn's Disease: A 9-Year Survival.

Small bowel adenocarcinoma is a rare but well-known complication of Crohn's disease. The diagnosis of small bowel adenocarcinoma remains difficult since its presentation is highly variable and mimics active or obstructive Crohn's disease. The diagnosis is often delayed and typically detected only at surgery in an advanced stage with a poor prognosis. We report a case of metastatic ileal adenocarcinoma in a patient with Crohn's disease with prolonged survival. Our case describes serial promising treatment options of these advanced malignancies and raises a possible role for checkpoint immunotherapy.

A Phase I-II Study Using Rexin-G Tumor-Targeted Retrovector Encoding a Dominant-Negative Cyclin G1 Inhibitor for Advanced Pancreatic Cancer.

Rexin-G is a replication-incompetent retroviral vector displaying a cryptic SIG-binding peptide for targeting abnormal Signature (SIG) proteins in tumors and encoding a dominant-negative human cyclin G1 construct. Herein we report on the safety and antitumor activity of escalating doses of Rexin-G in gemcitabine-refractory pancreatic adenocarcinoma, with one 10-year survivor. For the safety analysis (n = 20), treatment-related grade 1 adverse events included fatigue (n = 6), chills (n = 2), and headache (n = 1), with no organ damage and no DLT. No patient tested positive for vector-neutralizing antibodies, antibodies to gp70, replication-competent retrovirus (RCR), or vector integration into genomic DNA of peripheral blood lymphocytes (PBLs). For the efficacy analysis (n = 15), one patient achieved a complete response (CR), two patients had a partial response (PR), and 12 had stable disease (SD). Median progression-free survival (PFS) was 2.7, 4.0, and 5.6 months at doses 0-I, II, and III, respectively. Median overall survival (OS) and 1-year OS rate at dose 0-I were 4.3 months and 0%, and at dose II-III they were 9.2 months and 33.3%. To date, one patient is still alive with no evidence of cancer 10 years after the start of Rexin-G treatment. Taken together, these data suggest that Rexin-G, the first targeted gene delivery system, is uniquely safe and exhibits significant antitumor activity, for which the FDA granted fast-track designation.

Bevacizumab Added to Moderate-dose Chemotherapy for Refractory Uterine Cancer.

BACKGROUND/AIM: Bevacizumab (bev), when added to a moderate dose combination of previously failed cytotoxins, as a third- and fourth-line therapy for refractory gastric, cholangiocarcinoma, and ovarian cancers, produced high-quality responses. The regimen was based on preclinical models designed in order to simultaneously partner both bev and each of the cytotoxins with 4-5 synergistic drugs. PATIENTS AND METHODS: Eligible patients (n=9) had high-grade endometrial tumors and had failed standard chemotherapy. Bev (10 mg/kg every 2 weeks) and cyclophosphamide (150-250 mg/m2), were added to a combination of gemcitabine, fluorouracil, leucovorin, irinotecan and a platinum analogue -first without and then with docetaxel- each at approximately 1/2 to 1/3 of their standard dosage. Dose modification aimed at a repeated absolute neutrophil count (ANC) of 750-1,500 µl or platelets of 125,000-75,000 µl. Safety measures included stop-go use (intermittent, as needed, brief withholding of bev with resumption when again tolerated), of bev, and both prospective and ongoing dose modification in order to protect the bowels. RESULTS: Induction treatment was free of life-threatening complications. Nine consecutive patients, 3 under second- and 6 under multi-line treatment, had 9 objective responses and 8 produced long clinical benefits, 2 of which were complete responses. Seven responses created opportunities for personalized added treatment and research. Absolute median survival was 21.5 months for the 8 patients with platinum-resistant tumors. One patient was unable to tolerate a first standard adjuvant dose of paclitaxel. After rapid peritoneal progression of disease, treatment has produced 52+ months of unmaintained complete remission. CONCLUSION: Bev, in the combination that was used in this study, meets response, survival, and toxicity criteria for further testing against second- or multi-line chemotherapy-resistant tumors and also when a standard treatment is not safe.

Cancer of the Pancreas-Actual 5, 10, and 20+Year Survival: The Lucky and Fortunate Few.

Cancer of the pancreas (CaP) is a dismal, uncommon, systemic malignancy. This article updates an earlier experience of actual long-term survival of CaP in patients treated between 1991 to 2000, and reviews the literature. Survival is expressed as actual, not projected, survival.

Targeted Therapy for Resistant Cholangiocarcinoma with Bevacizumab or Cetuximab Added to Failed Cytotoxic Drug Cores.

BACKGROUND: Addition of bevacizumab/targeted therapy to cores consisting of four to five previously failed cytotoxic drugs employed at low/moderate dosages has produced third- and fourth-line regression of refractory gastric and ovarian cancer. Targeted therapy added to cores of previously failed drugs has similarly produced responses of refractory pancreatic cancer. PATIENTS AND METHODS: The aim of the present study was to evaluate the addition of targeted therapy to failed cores for patients with end-stage disease. Patients all had end-stage measurable cholangiocarcinoma and active progression during treatment with cores. Targeted therapy, bevacizumab or cetuximab, at standard dosages and schedule was added to the failed cores, which consisted of: gemcitabine, fluorouracil, leucovorin and irinotecan on day 1, and a platin with/without docetaxel on day 2, each at its prior dose and schedule. Electronic medical records facilitated identification of patients for intent-to-treat analysis. RESULTS: All 13 patients had measurable disease; all standard cytotoxins had been used and failed before the start of treatment with targeted therapy added to the cores. The response rates according to the Response Evaluation Criteria in Solid Tumors and response duration range were: bevacizumab cores: 3/6, 6 to 19 months, and cetuximab cores: 5/7, 10 to 28 months. Responses produced clinical benefit and one late neoadjuvant R0 resection. There were no limiting hematological adverse events due to the cores. Limiting adverse events were hypertension in two patients and an easily controlled duodenal ulcer in one. CONCLUSION: Bevacizumab cores and cetuximab cores both produced response rates which satisfy phase II criteria for further investigation. As cores, failed cytotoxic drugs, many at one-quarter to half of their standard doses have been found to produce synergistic benefit in combination with targeted therapy for end-stage patients in four diseases. Co-treatment with no longer active cytotoxic core drugs can demonstrate efficacy attributable to the targeted therapy. This approach is a worthy, cost-effective fast-track registration strategy and distinctly different from trials testing primary treatment.

Stereotactic radiosurgery plays a critical role in enhancing long-term survival in a patient with pancreatic cancer metastatic to the brain.

BACKGROUND: Pancreatic cancer is an aggressive disease which metastasizes readily. The presence of brain metastases from pancreatic cancer is rare and it carries a poor prognosis. Our approach to treating these lesions stresses extensive use of stereotactic radiosurgery (SRS), whereas other reports focus on surgical resection. CASE REPORT: Information regarding the patient's clinical history was extracted from a retrospective review of the medical records and imaging studies. The patient survived seven years after his primary diagnosis of pancreatic cancer, and 36 months after diagnosis of metastatic disease to the brain. In addition to surgical resection and the use of multiple chemotherapeutic agents, the patient received six separate radiosurgery treatments. CONCLUSION: We present a case of brain metastasis from pancreatic cancer that is remarkable for an unusually long survivorship and discuss the utility of SRS along with a multimodality treatment approach for dealing with these cases.

Pathotropic nanoparticles for cancer gene therapy Rexin-G IV: three-year clinical experience.

Metastatic cancer is a life-threatening illness with a predictably fatal outcome, thereby representing a major unmet medical need. In 2003, Rexin-G became the world's first targeted injectable vector approved for clinical trials in the treatment of intractable metastatic disease. Uniquely suited, by design, to function within the context of the human circulatory system, Rexin-G is a pathotropic (disease-seeking) gene delivery system bearing a designer killer gene; in essence, a targeted nanoparticle that seeks out and selectively accumulates in metastatic sites upon intravenous infusion. The targeted delivery of the cytocidal gene to primary tumors and metastatic foci, in effective local concentrations, compels both cancer cells and tumor-associated neovasculature to self-destruct, without causing untoward collateral damage to non-target organs. In this study: i) we report the results of three distinctive clinical studies which demonstrate the initial proofs of concept, safety, and efficacy of Rexin-G when used as a single agent for advanced or metastatic cancer, ii) we introduce the quantitative foundations of an innovative personalized treatment regimen, designated the 'Calculus of Parity', based on a patient's calculated tumor burden, iii) we propose a refinement of surrogate end-points commonly used for defining success in cancer therapy, and iv) we map out a strategic plan for the accelerated approval of Rexin-G based on the oncologic Threshold of Credibility paradigm being developed by the Food and Drug Administration.

Bevacizumab as treatment for chemotherapy-resistant pancreatic cancer.

A 74-year-old male, with refractory stage IV pancreatic cancer, was successfully treated with bevacizumab 5 mg/kg and combination chemotherapy consisting of gemcitabine, fluorouracil leucovorin, irinotecan and cisplatin (GFLIP) every two weeks. The patient had rapidly failed initial treatment with GFLIP given in an identical dose and schedule. Large new liver lesions developed during active treatment. On adding bevacizumab to GFLIP, serial measures on CT confirmed an objective (RECIST) response. The tumor marker CA19-9 fell rapidly from 24,000 U/ml to less than 400 U/ml. This was accomplished with clinically inconsequential side-effects. This is the first demonstrated benefit of bevacizumab used in combination with previously failed chemotherapy for pancreatic cancer.

Biweekly low-dose sequential gemcitabine, 5-fluorouracil, leucovorin, and cisplatin (GFP): a highly active novel therapy for metastatic adenocarcinoma of the exocrine pancreas.

Phase II studies have suggested an improved response rate and acceptable toxicity profile associated with gemcitabine combinations compared to gemcitabine alone for treatment of metastatic adenocarcinoma of the pancreas. The GFP regimen (gemcitabine, 5-fluorouracil, leucovorin, and cisplatin) is based on laboratory evidence of disease-specific chemotherapy interaction. This retrospective analysis examined the outcome of 49 consecutive patients with histologically confirmed metastatic pancreatic adenocarcinoma treated between July 1998 and September 2000. Day 1 treatment consisted of gemcitabine 500 mg/m2 over 30 minutes and then leucovorin 300 mg bolus, 5-fluorouracil (5-FU) 400 mg/m2 bolus, followed by infusional 5-FU 600 mg/m2 over 8 hours. Day 2 consisted of leucovorin 300 mg bolus, 5-FU 400 mg/m2 bolus, followed by cisplatin 50-75 mg/m2 over 30 minutes and then infusional 5-FU 600 mg/m2 over 8 hours. Treatment was administered every 2 weeks. Median patient age was 61.5 years, 74% were men, and 20 patients had refractory disease (11 patients had disease progression upon gemcitabine-based therapy). Grade 3-4 toxic effects (% patients) consisted of neutropenia (30%), thrombocytopenia (14%), anemia (8%), and neutropenic fever (2%). Grade 3-4 nonhematological toxicities (% patients) consisted of neuropathy (14%), ototoxicity (8%), nephrotoxicity (6%), nausea/vomiting (14%), and mucositis (10%). The majority of dose reductions were made for neuropathy or cytopenias. Filgrastim and erythropoietin were given as needed to promote dose intensity. Eight patients attained a partial response (PR) by RECIST criteria. Fourteen had stable disease (SD). Two patients attaining PR and two attaining SD had progressive disease with prior gemcitabine-based therapy. The median time to disease progression (TTP) from GFP start was 9 weeks. For all 49 patients, the median overall survival (OS) from GFP start was 10.6 months, 12-month survival was 46%, and 24-month survival was 30%. Notably, upon disease progression, 31 patients continued to receive the GFP regimen with irinotecan 80 mg/m2 inserted on day 1 following gemcitabine, the G-FLIP regimen (gemcitabine, 5-fluorouracil, leucovorin, irinotecan, and cisplatin). Measured from G-FLIP initiation, the TTP for the 31 patients treated sequentially was 10 weeks, and for the 14 patients attaining SD or PR the TTP was 25 weeks. The median overall survival measured from GFP initiation was 11.8 months. The response rate, non-cross resistance, TTP, OS, and tolerability warrant prospective development of this novel combination. This experience also demonstrates that adding a single new drug such as irinotecan to the same first-line chemotherapy combination upon disease progression may be an important alternative for the treatment of relapsed/resistant cancer.

ATP chemosensitivity testing in ovarian and breast cancer: early clinical trials.

After disappointing results achieved with older chemosensitivity tests such as the human tumor clonogenic assay (HTCA) during the 1980s, the last decade has seen a renaissance of the concept of individualized chemotherapy in oncology, markedly stimulated by the development of newer nonclonogenic assays. These methods appear to be able to overcome major technical limitations associated with older assays, now allowing for successful testing of most of the tumor specimens submitted. Currently, the ATP-based tumor chemosensitivity assay (ATP-TCA) can be regarded as the most sophisticated assay to investigate both solid samples and effusions derived from patients with various organ tumors. During the last 5 years, the ATP-TCA has been used successfully to screen for novel drug combinations for further clinical use in both ovarian and breast cancer such as mitoxantrone plus paclitaxel (NT) and treosulfan plus gemcitabine (TG), respectively. Clinical trials that have been set up in heavily pretreated patients with recurrent ovarian or breast cancer have convincingly confirmed the high activity of these combinations previously demonstrated in preclinical investigations using the ATP-TCA. In a recent phase II trial performed in 59 patients with relapsed ovarian carcinoma, ATP-TCA-directed therapy was able to triple the response rate and to double the survival time, compared with published empirical chemotherapy regimes. Preliminary results with ATP-TCA-directed therapy in breast cancer also evidenced promising response rates. These results have been confirmed by additional prospective clinical trials using other types of modern nonclonogenic assays. A phase III trial that is now actively recruiting patients with platinum-refractory ovarian cancer to verify the promising phase II studies will prove the further value of the ATP-TCA as a predictor applicable in routine clinical oncology.

A comprehensive update on the use of chemotherapy for metastatic pancreatic adenocarcinoma.

Phase II trials of combination chemotherapies have shown encouraging palliative benefit, objective response rates, and survival outcomes. Until ongoing phase III trials confirm these benefits, the current standard treatment for metastatic pancreatic adenocarcinoma remains single agent gemcitabine. The fixed rate infusion schedule of 10 mg/m2/min is gaining wide acceptance and is a promising investigational priority. A very reasonable alternative to single agent gemcitabine, and our bias, is enrollment into clinical trials evaluating novel gemcitabine-based combinations. Further investigation is needed to determine optimal incorporation of so-called targeted therapy with combination chemotherapy.

Irinotecan plus gemcitabine induces both radiographic and CA 19-9 tumor marker responses in patients with previously untreated advanced pancreatic cancer.

PURPOSE: This phase II, multicenter, open-label, single-arm study evaluated the efficacy and safety of irinotecan and gemcitabine as combination chemotherapy for previously untreated patients with unresectable or metastatic pancreatic cancer. PATIENTS AND METHODS: Patients received repeated 21-day cycles at starting doses of gemcitabine 1,000 mg/m(2) over 30 minutes followed immediately by irinotecan 100 mg/m(2) over 90 minutes, both given intravenously on days 1 and 8. Patients were evaluated for objective tumor response, changes in the serum tumor marker CA 19-9, time to tumor progression (TTP), survival, and safety. RESULTS: Forty-five patients were treated. Eleven patients (24%) had 50% or greater reductions in tumor area. These were confirmed one cycle later in nine patients (response rate, 20%; 95% confidence interval, 8% to 32%). Among 44 patients with baseline CA 19-9 determinations, CA 19-9 decreased during therapy in 22 patients (50%) and was reduced by 50% or more in 13 patients (30%). Median TTP was 2.8 months (range, 0.3 to 10.8 months). There were significant (P <.001) correlations between proportional changes in CA 19-9 and radiographic changes in tumor area with regard to extent of change (r =.67), timing of minimum on-study values (r =.85), and tumor progression (r =.89). Median survival was 5.7 months (range, 0.4 to 19.4+ months), and the 1-year survival rate was 27%. Severe toxicities were uncommon and primarily limited to grade 4 neutropenia (2%), grade 4 vomiting (2%), and grade 3 diarrhea (7%). CONCLUSION: Irinotecan/gemcitabine is a new combination that offers encouraging activity in terms of radiographic and CA 19-9 response and notable 1-year survival in pancreatic cancer. The regimen was well tolerated, with minimal grade 3 and 4 toxicities and excellent maintenance of planned dose-intensity.

Adjuvant and Neoadjuvant Therapies of Pancreatic Cancer: A Review.

The survival of patients diagnosed with pancreatic cancer is dismal. Few patients on initial presentation aresuitable for surgical resection. This has prompted clinical studies with chemotherapy and/or radiotherapydesigned either to increase the number of patients eligible for surgery (neoadjuvant therapy) or to prolong thesurvival of patients who had undergone surgery (adjuvant therapy). None of these studies may at this time beconsidered definitive. Wherever possible, patients felt eligible for neoadjuvant or adjuvant therapy should beentered on clinical trials. Where this is not possible, clinicians should exercise their best judgment in offeringthis type of treatment to pancreatic cancer patients under their care.