Francesca Fiorentino

Pulmonary metastasectomy: what is the practice and where is the evidence for effectiveness?

Pulmonary metastasectomy is a commonly performed operation and is tending to increase as part of a concept of personalised treatment for advanced cancer. There have been no randomised trials; belief in effectiveness of metastasectomy is based on registry data and surgical follow-up studies. These retrospective series are comprised predominately of solitary or few metastases with primary resection to metastasectomy intervals longer than 2–3 years. Five-year survival rates of 30–50% are recorded, but as case selection is based on favourable prognostic features, an apparent association between metastasectomy and survival cannot be interpreted as causation. Cancers for which lung metastasectomy is used are considered in four pathological groups. In non-seminomatous germ cell tumour, for which chemotherapy is highly effective, excision of residual pulmonary disease guides future treatment and in particular allows an informed decisions as to further chemotherapy. Sarcoma metastasises predominately to lung and pulmonary metastasectomy for both bone and soft tissues sarcoma is routinely considered as a treatment option but without randomised data. The commonest circumstance for lung and liver metastasectomy is colorectal cancer. Repeated resections and ablations are commonplace but without evidence of effectiveness for either. For melanoma, results are particularly poor, but lung metastases are resected when no other treatment options are available. In this review, the available evidence is considered and the conclusion reached is that in the absence of randomised trials there is uncertainty about effectiveness. A randomised controlled trial, Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC), is in progress and randomised trials in sarcoma seem warranted.

Pulmonary metastasectomy for sarcoma: a systematic review of reported outcomes in the context of Thames Cancer Registry data

Objectives Sarcoma has a predilection to metastasis to the lungs. Surgical excision of these metastases (pulmonary metastasectomy) when possible has become standard practice. We reviewed the published selection and outcome data. Design Systematic review of published reports that include survival rates or any other outcome data. Survival data were put in the context of those in a cancer registry. Setting Specialist thoracic surgical centres reporting the selection and outcome for pulmonary metastasectomy in 18 follow-up studies published 1991–2010. Participants Patients having one or more of 1357 pulmonary metastasectomy operations performed between 1980 and 2006. Interventions All patients had surgical pulmonary metastasectomy. A first operation was reported in 1196 patients. Of 1357 patients, 43% had subsequent metastasectomy, some having 10 or more thoracotomies. Three studies were confined to patients having repeated pulmonary metastasectomy. Primary and secondary outcome measures Survival data to various time points usually 5 years and sometimes 3 or 10 years. No symptomatic or quality of life data were reported. Results About 34% and 25% of patients were alive 5 years after a first metastasectomy operation for bone or soft tissues sarcoma respectively. Better survival was reported with fewer metastases and longer intervals between diagnosis and the appearance of metastases. In the Thames Cancer Registry for 1985–1994 and 1995–2004 5 year survival rates for all patients with metastatic sarcoma were 20% and 25% for bone, and for soft tissue sarcoma 13% and 15%. Conclusions The 5 year survival rate among sarcoma patients who are selected to have pulmonary metastasectomy is higher than that observed among unselected registry data for patients with any metastatic disease at diagnosis. There is no evidence that survival difference is attributable to metastasectomy. No data were found on respiratory or any other symptomatic benefit. Given the certain harm associated with thoracotomy, often repeated, better evidence is required.

The CEA Second-Look Trial: a randomised controlled trial of carcinoembryonic antigen prompted reoperation for recurrent colorectal cancer.

Objective In patients who have undergone a potentially curative resection of colorectal cancer, does a ‘second-look’ operation to resect recurrence, prompted by monthly monitoring of carcinoembryonic antigen, confer a survival benefit? Design A randomised controlled trial recruiting patients from 1982 to 1993 was recovered under the Restoring Invisible and Abandoned Trials (RIAT) initiative. Setting 58 hospitals in the UK. Participants From 1982 to 1993, 1447 patients were enrolled. Of these 216 met the criteria for carcinoembryonic antigen (CEA) elevation and were randomised to ‘Aggressive’ or ‘Conventional’ arms. Interventions ‘Second-look’ surgery with intention to remove any recurrence discovered. Primary outcome measure Survival. Results By February 1993, 91/108 patients had died in the ‘Aggressive arm’ and 88/108 in the ‘Conventional’ arm (relative risk=1.16, 95% CI 0.87 to 1.37). By 2011 a further 25 randomised patients had died. Kaplan-Meier analysis showed no difference in long-term survival. Conclusions The trial was closed in 1993 following a recommendation from the Data Monitoring Committee that it was highly unlikely that any survival advantage would be demonstrated for CEA prompted second-look surgery. This conclusion was confirmed by repeat analysis of survival times after 20 years. Trial registration number ISRCTN76694943.

Pulmonary metastasectomy in colorectal cancer: a prospective study of demography and clinical characteristics of 543 patients in the Spanish colorectal metastasectomy registry (GECMP-CCR)

Objectives To capture an accurate contemporary description of the practice of pulmonary metastasectomy for colorectal carcinoma in one national healthcare system. Design A national registry set up in Spain by Grupo Español de Cirugía Metástasis Pulmonares de Carcinoma Colo-Rectal (GECMP-CCR). Setting 32 Spanish thoracic units. Participants All patients with one or more histologically proven lung metastasis removed by surgery between March 2008 and February 2010. Interventions Pulmonary metastasectomy for one or more pulmonary nodules proven to be metastatic colorectal carcinoma. Primary and secondary outcome measures The age and sex of the patients having this surgery were recorded with the number of metastases removed, the interval between the primary colorectal cancer operation and the pulmonary metastasectomy, and the carcinoembryonic antigen level. Also recorded were the practices with respect to mediastinal lymphadenopathy and coexisting liver metastases. Results Data were available on 543 patients from 32 units (6–43/unit). They were aged 32–88 (mean 65) years, and 65% were men. In 55% of patients, there was a solitary metastasis. The median interval between the primary cancer resection and metastasectomy was 28 months and the serum carcinoembryonic antigen was low/normal in the majority. Liver metastatic disease was present in 29% of patients at some point prior to pulmonary metastasectomy. Mediastinal lymphadenectomy varied from 9% to 100% of patients. Conclusions The data represent a prospective comprehensive national data collection on pulmonary metastasectomy. The practice is more conservative than the impression gained when members of the European Society of Thoracic Surgeons were surveyed in 2006/2007 but is more inclusive than would be recommended on the basis of recent outcome analyses. Further analyses on the morbidity associated with this surgery and the correlation between imaging studies and pathological findings are being published separately by GECMP-CCR.

Pharmacokinetics, adverse effects and tolerability of a novel analogue of human pancreatic polypeptide, PP 1420

AIMS The objectives of this phase 1 study were to confirm the tolerability of single ascending subcutaneous doses of PP 1420 in healthy subjects, to assess its adverse effects and to investigate the drugs pharmacokinetics and dose proportionality. METHODS This was a double-blind, placebo-controlled, randomized study. There were three dosing periods. Each subject (n= 12) was randomized to receive one dose of placebo and two ascending doses of PP 1420, given as a subcutaneous injection. Blood samples were taken over 24 h to assess pharmacokinetics. Standard safety and laboratory data were collected. The primary endpoint was the tolerability of PP 1420. The secondary endpoint was exposure to PP 1420 as assessed by C(max) and AUC(0,∞). RESULTS PP 1420 was well tolerated by all subjects with no serious adverse effects. Following single subcutaneous doses of PP 1420 at 2, 4 and 8 mg to male subjects, C(max) was reached at a median t(max) of approximately 1 h post dose (range 0.32-2.00 h). Thereafter, plasma concentrations of PP 1420 declined with geometric mean apparent terminal elimination t(1/2) ranging from 2.42-2.61 h (range 1.64-3.95 h) across all dose levels. CONCLUSIONS Subcutaneous PP 1420 was well tolerated in healthy human subjects at single doses between 2-8 mg, with no tolerability issues arising. Where observed, adverse events were not serious, and there was no evidence of a dose-relationship to frequency of adverse events. The results therefore support the conduct of clinical trials to investigate efficacy, tolerability and pharmacokinetics during repeated dosing.

Coronary Artery-Bypass-Graft Surgery Increases the Plasma Concentration of Exosomes Carrying a Cargo of Cardiac MicroRNAs: An Example of Exosome Trafficking Out of the Human Heart with Potential for Cardiac Biomarker Discovery.

Introduction Exosome nanoparticles carry a composite cargo, including microRNAs (miRs). Cultured cardiovascular cells release miR-containing exosomes. The exosomal trafficking of miRNAs from the heart is largely unexplored. Working on clinical samples from coronary-artery by-pass graft (CABG) surgery, we investigated if: 1) exosomes containing cardiac miRs and hence putatively released by cardiac cells increase in the circulation after surgery; 2) circulating exosomes and exosomal cardiac miRs correlate with cardiac troponin (cTn), the current “gold standard” surrogate biomarker of myocardial damage. Methods and Results The concentration of exosome-sized nanoparticles was determined in serial plasma samples. Cardiac-expressed (miR-1, miR-24, miR-133a/b, miR-208a/b, miR-210), non-cardiovascular (miR-122) and quality control miRs were measured in whole plasma and in plasma exosomes. Linear regression analyses were employed to establish the extent to which the circulating individual miRs, exosomes and exosomal cardiac miR correlated with cTn-I. Cardiac-expressed miRs and the nanoparticle number increased in the plasma on completion of surgery for up to 48 hours. The exosomal concentration of cardiac miRs also increased after CABG. Cardiac miRs in the whole plasma did not correlate significantly with cTn-I. By contrast cTn-I was positively correlated with the plasma exosome level and the exosomal cardiac miRs. Conclusions The plasma concentrations of exosomes and their cargo of cardiac miRs increased in patients undergoing CABG and were positively correlated with hs-cTnI. These data provide evidence that CABG induces the trafficking of exosomes from the heart to the peripheral circulation. Future studies are necessary to investigate the potential of circulating exosomes as clinical biomarkers in cardiac patients.

Pulmonary metastasectomy for colorectal cancer: Making the case for a randomized controlled trial in the zone of uncertainty

Survival after pulmonary metastasectomy, from the earliest to the most recent reports, has been related to the number of metastases and the time to their appearance. The fewer the metastases and the longer the interval between primary surgery and metastasectomy, the better is survival. 1 Many clinical reports (by now there are>100 for colorectal cancer) have implied that survival is gained by pulmonary metastasectomy and have encouraged widening the indications. A survey of members of the European Society of Thoracic Surgeons, from November 2006 through January 2007, found that the large majority of responding surgeons (86%) placed no upper limit on the number of pulmonary metastases they were prepared to resect and 64% would perform a metastasectomy within a year of the primary cancer surgery. 2 An alternative explanation for the association between metastasectomy and longer survival is that careful selection of patients with favorable prognostic features, which is central to the management of these patients, gathers in patients likely to survive longer. Observational studies with larger numbers of patients and better statistical analyses have shown that the old rules still apply and a more liberal implementation of pulmonary metastasectomy is associated with diminishing returns or worse, and it becomes evident that benefit in these patients is improbable and therefore they should be excluded. 1,3 In this brief review we examine observational data and mathematic modeling. We conclude that a clinical trial, focusing on the zone of uncertainty, is needed. The Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC) trial, based on that reasoning, is recruiting patients in Europe (http://www. rbht.nhs.uk/research/cteu/projects/respiratory-disease/ pulmicc/).

Operating to remove recurrent colorectal cancer: have we got it right?

A randomised controlled trial that remained unpublished for 20 years casts doubt on the survival benefit of further surgery after curative resection of colorectal cancer. Tom Treasure and colleagues tell the story of the first trial restored under the restoring invisible and abandoned trials initiative and discuss what it means today

Meta‐analysis of colorectal cancer follow‐up after potentially curative resection

After potentially curative resection of primary colorectal cancer, patients may be monitored by measurement of carcinoembryonic antigen and/or CT to detect asymptomatic metastatic disease earlier.

Survival is higher after repeat lung metastasectomy than after a first metastasectomy: Too good to be true?

The authors of the International Registry of Lung Metastases reported that survival was higher for a second compared with a first metastasectomy operation after 5 and 10 years (44% vs 39% and 29% vs 25%, respectively). Pastorino and colleagues wrote ‘‘The long-term outcome of patients who were treated by a second metastasectomy was remarkably good.’’ The word ‘‘remarkably’’ provides the clue. The finding seemed to be too good to be true. Similar observations have been made repeatedly for sarcoma, which is the most established clinical indication for lung metastasectomy. In a systematic review of 14 followup studies composed of 1357 patients, 579 received a repeat metastasectomy (43%; range, 21%-79%). The observation that repeat metastasectomy was followed by higher survival has been made repeatedly.