December 2009

Current Topics in Sarcoma: A Review of Recent Articles

An ESUN Feature

Elizabeth Goldstein-Rice

Contents:
Stress of Adolescent Children of Parents with Cancer Underestimated by Parents

"Stress response symptoms in adolescents during the first year after a parent’s cancer diagnosis." Gea A. Huizinga, Annemieke Visser, Winette T. A. van der Graaf, Harald J. Hoekstra, Stacey M. Gazendam-Donofrio, Josette E. H. M. Hoekstra-Weebers.

This study, made possible by a grant from the Dutch Cancer Society, examines the effect on adolescents of having a parent diagnosed with cancer.  The team of researchers from the University Medical Center Groningen, Radboud University Nijmegen Medical Center and the Comprehensive Cancer Centre North-East Netherlands, describe the purpose of this study, saying, "This work aims to prospectively study stress response symptoms (SRS) in adolescents during the first year after a parent’s cancer diagnosis and factors associated with SRS. Additionally, SRS in these adolescents were compared to SRS in adolescents whose parents were diagnosed 1–5 years (reference group) previously."  The expected results of the study varied from the actual results as described below.

Symptoms of SRS
"Children with SRS often experience other emotional and behavioral problems such as depression, somatic complaints, aggressive or delinquent behavior, and cognitive problems [7, 8] that may hinder their normal development [9]."

Participation
Approached:  222
Consented:    112
Reference:    174
The reference group was composed of those whose parents had been diagnosed with cancer 1-5 years earlier.

Participation over time

Time                                          # Participants
T1: 4 months after diagnosis         68 families
T2: 6 months after diagnosis         44 families
T3: 12 months after diagnosis       37 families

Measures used to assess adolescent SRS included the IES, YSR and CBCL
YSR    Youth Self-Report
CBCL   Child Behavior Checklist
IES     Impact of Event Scale

Expected Results
"Based on the literature, we hypothesized that: (1) SRS will be high in adolescents shortly following the parent’s cancer diagnosis and that symptoms decrease during the first year; (2) SRS in adolescents throughout the first year will be higher than SRS levels of adolescents whose parents were diagnosed 1–5 years previously; (3) daughters, older adolescents, those whose mother had cancer, or whose parent received a more intensive or longer treatment will be more vulnerable; (4) SRS coincide with emotional and behavioral problems; and (5) initial SRS predict later SRS and other emotional/behavioral problems."

Actual Results
The authors summarize the actual results, saying, "Clinically elevated SRS were found in 29% of adolescents at T1, 16% at T2, and 14% at T3. In contrast, in the reference group, we found 29% clinically elevated SRS.  Daughters seemed more at risk than sons. Adolescents’ age, patient’s gender, and intensity and duration of treatment did not significantly affect SRS. Adolescents with more SRS reported having more emotional/behavioral problems.  Parents observed fewer problems in those adolescents.  Initial SRS affected later SRS and emotional problems.  Conclusions: The findings illustrate that adolescent children of cancer patients may have clinically elevated SRS that are associated with emotional and behavioral problems. The prevalence of such problems may be underestimated by the parents."

It appears that parents of these adolescents frequently perceive that their children are handling a parent’s illness better than they really are.  Parents should take note and talk to their teens openly and honestly about their feelings to ensure they aren’t hiding their distress behind a brave face.

References included in citations in this summary
7. Saigh PA, Yasik AE, Oberfield RA, Halamandaris PV, McHugh M (2002) An analysis of the internalizing and externalizing behaviors of traumatized urban youth with and without PTSD. J Abnorm Psychol 111:462–470

8. Yule W (2001) Posttraumatic stress disorder in the general population and in children. J Clin Psychiatry 17(62 Suppl):23–28

9. Davis L, Siegel LJ (2000) Posttraumatic stress disorder in children and adolescents: A review and analysis. Clin Child Fam Psychol Rev 3:135–154


Cancer During Pregnancy: An Analysis of 215 Patients Emphasizing the Obstetrical and the Neonatal Outcomes

Authors: Kristel Van Calsteren, Liesbeth Heyns, Frank De Smet, Liesbet Van Eycken, Mina Mhallem Gziri, Willemijn Van Gemert, Michael Halaska, Ignace Vergote, Nelleke Ottevanger, and Frederic Amant

The purpose of this study, published by the Journal of Clinical Oncology, was "to assess the management and the obstetrical and neonatal outcomes of pregnancies complicated by cancer."  Records selected for the study were from patients diagnosed with invasive cancer while pregnant during the 10-year period between 1998 and 2008.   In cases like these, patients and physicians must weigh the benefits of treatment during pregnancy against the risks of negative outcomes for either mother or child.  The authors note that the decision is often made to terminate the pregnancy.  Patients who decide to proceed with the pregnancy may not receive the best treatment because of the potential risks associated with chemotherapy and radiation.  The authors point out that more women will be diagnosed with cancer while pregnant in part because of the trend to have children later in life, between the ages of 30-49.  It has been found that cancer occurrences during this age span is increasing. 

The tumor types found in the selected records included breast cancer, hematologic malignancies, dermatologic malignancies, cervical cancer, brain tumors, ovarian cancer, colorectal cancer and the ever-present Other, which includes sarcomas.  Cases ending with miscarriage or abortion were not included in the study, reducing the number of records to be analyzed to 180. 

Notable Excerpts
"The most remarkable finding is the observation that 54.2% of children were born preterm, with a subsequently high rate of admission to the NICU. In the vast majority (89.7%), the delivery was iatrogenically induced. The complications of preterm birth are well studied ... preterm birth is also associated with long-term morbidities and impaired cognitive and behavioral outcomes.  In this study, neonatal problems were mainly due to iatrogenic, and therefore preventable, prematurity. Prematurity can be prevented by postponing or continuing treatment until a term delivery can be obtained."

"Deliberate delay of therapy to achieve fetal maturity appears to be a safe option for patients with early-stage disease."

"no evidence for a survival benefit due to early initiation of adjuvant chemotherapy within the first 2 to 3 months after surgery"

"Continuation of treatment started during pregnancy is a second way to prevent prematurity. To date, treatment during pregnancy is continued until fetal viability is reached. Instead, fetal maturity should preferably be the criterion to induce delivery. In a multidisciplinary setting, a maximal effort should be made to delay delivery until at least 35 to 37 weeks."

"The largest proportion of small-for-gestational-age children was seen in patients with hematologic tumors."

"Malformations that were reported in this study are also seen in a normal population. Furthermore, the incidence was not increased."

"impact on fetal growth might be related to specific cancer types and treatments"

"Physical or psychological stress can induce preterm labor through activation of the maternal hypothalamic-pituitary-adrenal axis; thus, the stress associated with cancer diagnosis and treatment may contribute."

"An important strength of this study is that a large series of only invasive cancers diagnosed during pregnancy was included (excluding preinvasive and postpartum diagnoses). Furthermore, the interpretation of the birth weight was adjusted for gestational age and sex. Limitations to our study include the absence of centralized national registries for the entity ‘cancer and pregnancy’."

Regarding Complications
51.2% of children required hospitalization in NICU, primarily due to prematurity (85.2%).  Congenital anomolies were found in 3.4%, dysmaturity in 3.4% and respiratory insufficiency in 1.1%.  6.8% were admitted for observation.

The Authors’ Conclusion
"The findings of this study show an overall good outcome of pregnancies complicated with cancer. However, a high rate of preterm labor induction with a subsequent high rate of admission of infants to the NICU was observed. Interdisciplinary decision making on the timing of delivery by obstetricians and neonatologists is necessary. Preferably, delivery should not be induced before 35 to 37 weeks."

Useful Definitions


An exploration of the experience of cancer cachexia: what patients and their families want from healthcare professionals

Reid, J., McKenna, H. P., Fitzsimons, D. and McCance T., (2009) European Journal of Cancer Care.

The stated goal of this paper is to "investigate the perceptions of patients and family members with regard to care received for cancer cachexia" (physical wasting with loss of weight and muscle mass caused by disease).  27 participants were recruited from a regional cancer center in the UK, including 15 cancer patients with advanced disease and 12 family members.   The symptoms of cachexia include extreme loss of weight, wasting of muscle mass, cancer-related anorexia, feelings of being full before consuming sufficient food, weakness, low levels of oxygen in the blood, and excess fluid retention.

Interviews were conducted in the family home.  A major response from participants was that they were frustrated by the "lack of response from health care professionals".  What the family members wanted from healthcare professions in regard to cachexia:

The authors cite research which found that the problem with cachexia when it occurs with primary cancers is that eating does not address the problem (Barber & Rogers 2002).  Although the condition is likely caused by metabolic changes caused by the cancer (Martignoni et al. 2003), the fact that healthcare professionals did not discuss or address the obvious issue, patients often felt that they had done something wrong.  Not many studies have been done on the subject to provide not only a better understanding of what treatments work, but also the psychological impacts to patients and their families.

Interventions usually focus on the use of pharmaceuticals or referral of the patient to a dietician.  Regarding pharmacological treatments, the authors state, "Even if a pharmacological agent were produced that minimized the weight loss associated with cancer cachexia, it is likely that it would still prevail and require professional input (Poole & Froggatt 2002)."  In the discussion of possible interventions the authors recognize that physicians may not have much to offer.  They state, "Indeed, practice guidelines detailing the most advantageous therapeutic treatment modality for cancer cachexia have yet to be determined. This may help to explain the silent response from healthcare professionals, as perceived by participants within the present study." 

However, this silence added to the participants’ sense of isolation, feelings of being overwhelmed and fears that medical staff did not have the knowledge and skills needed to manage their case.  The authors propose that even though options are limited, "The provision of such information would help patients and their family members understand that weight loss is an irreversible outcome of cachexia and comprehend that treatment options are limited. Ongoing patient focused communication between patient, family member and healthcare professional could provide a basis for this much needed information exchange."

Useful Definitions

References
Barber M.D. & Rogers B.B. (2002) Advances in the Management of Tumour Induced Weight Loss.

Martignoni M.E., Kunze P. & Friess H. (2003) Cancer Cachexia.  Molecular Cancer 2, 36–41.

Poole K. & Froggatt K. (2002) Loss of weight and loss of appetite in advanced cancer: a problem for the patient, the carer, or the health professional. Palliative Medicine 16, 499–506.


More Information From the Paraffin Block

"Expression of M-CSF and CSF-1R is Correlated with Histological Grade in Soft Tissue Tumors." Elin Richardsen, Sveinung Wergeland Sørbye, John Phil Crowe, Jia-Lin Yang, and Lill-Tove Busund.

In this study, researchers from Norway, New South Wales and Australia examine the effect of binding between M-CSF (macrophage colony stimulating factor) and CSF-1R (colony stimulating factor-1 receptor) in soft tissue tumors.  The researchers state that this process "stimulates the proliferation, differentiation and behaviour of monocytes, macrophages and their bone marrow progenitors."   They go on to note that "Previous studies have suggested that high expression of these markers is correlated with poor prognosis." 

The information obtained through studies like this one help in the early diagnosis and grading of sarcoma tumors.  It serves as valuable input into the treatment plan and prognostics, helping physicians select chemo, radiation, and surgery treatments appropriate for each patient.   It is a challenge for pathologists to obtain this detailed information from tissue samples taken during initial diagnosis and follow-ups.  It is also useful to confirm the results of earlier studies and hypotheses as new technologies emerge.

The researchers performed analysis using immunohistochemistry – the process of using antibodies to find protein in tissues.  Tissue samples, embedded in paraffin, were obtained from 46 patients diagnosed at the Prince of Wales Hospital in Syndey, Australia.  39 had not undergone any treatment at the time the tissue was collected.  7 had been diagnosed with GIST (gastrointestinal stromal tumor).   The grade (1, 2, 3) of each tumor was determined according to the FNCLCC (French Federation of Cancer Centers Sarcoma Group) system, with the exception of the GIST tumors, which was graded using criteria from WHO.

Regarding the methodology used, the authors summarize, "The proportion of positive cells and the expression intensity of M-CSF, CSF-1R and CD68 in both the tumor cell areas and the adjacent stromal areas were correlated to the histological grade."  The discussion of the background and details of how the study was carried out are wholly technical, so this author will jump to the results.  The authors summarize that, "In the high grade tumors M-CSF and CSF-1R were more highly expressed than in the low grade tumors. This was seen in both the tumor cell areas and the adjacent stromal areas.  No differences in CD68 expression between the high and low grade tumors were found either in the tumor cell areas or the stromal areas."

The authors conclude that there is a relationship between the "expression of M-CSF and CSF-1R in tumor cell areas and adjacent stromal areas" and tumor grade.  In this way, the grade of a tumor can be discovered or fine-tuned during tissue analysis.

Useful Definitions


FDG PET Imaging of Childhood Sarcomas

Rajen J. Mody, MD, MS, Chuong Bui, MD, Raymond J. Hutchinson, MD, MS, Greg A. Yanik, MD, Valerie P. Castle, MD, Kirk A. Frey, MD, PhD, and Barry L. Shulkin, MD, in Pediatr Blood Cancer DOI 10.1002.

The authors of this article examined 46 scans taken for 25 patients over the course of 12 years.  The goal was to evaluate the usefulness of positron-emission tomography (PET) imaging using fluorodeoxyglucose (FDG) in managing the care of children and young adults with childhood sarcomas.  Three machine types were used to acquire the images: Siemens CTI 931, Siemens Exact or Siemens HR+PET scanner.  In describing the methodology used, the authors state, "Sites of abnormal uptake were considered as focal accumulations greater than surrounding background not explained by normal organ uptake. Only standard uptake value (SUV) max is reported since that value is the most reproducible among the SUV options. SUVs could not be determined on tumors that did not contain elevated concentrations of FDG nor on scans stored on computer systems that are no longer operational."  Two reviewers examined the images independently without knowing the details of the cases.

Patient details provided include distribution by diagnosis and treatment phase and the number of scans over time.  According to the authors, "Sensitivity, specificity, positive predictive value, and negative predictive value were calculated for PET performance based on results of other scans, clinical follow-up, and biopsy results if available."  

Some interesting findings

FDG PET was found to be advantageous in the following scenarios:

False positives resulted for:

Because sarcomas are so sneaky, uptake could not be determined in some patients because either the focal point of the tumor was inactive and not detected by PET alone or because the disease in the bone marrow was spread out such that there was no specific point of abnormal uptake.

The authors summarize their findings, saying "we have found FDG PET useful in the staging and management of EFST and rhabdomyosarcoma in children. Further studies are currently under way to systematically evaluate the utility of the technique in greater numbers of children and being treated on similar or identical protocols. We anticipate that advances in technology and refinement of FDG PET and FDG PET CT techniques will further aid in the management of children and young adults with ESFT and rhabdomyosarcomas."


Survival in high-grade osteosarcoma: improvement over 21 years at a single institution

P. Picci, M. Mercuri, S. Ferrari, M. Alberghini, A. Briccoli, C. Ferrari1, E. Pignotti & G. Bacci

The group of researchers from the Istituto Ortopedico Rizzoli, listed above describes the goals of this study as "to analyze improvements in overall survival over 21 years (1982–2002), with a 5-year minimum follow-up, in the largest series from a single center ever reported."  They go on to say they are "trying to evaluate possible improvement in prognosis and, if that is the case, to analyze which patients benefited most from this improvement."

They start by compiling a large set of records of patients with high-grade osteosarcoma, without regard to patient’s sex, affected site, stage of disease or histological type of cells were involved.  This paper provides the results of extensive analysis, highlights of which are summarized below.

Data is reported for participants designated as "patients candidates for protocols" vs "patients non-candidates to protocols."  The protocols used for these patients all included chemotherapy before surgery.  The chemo agents used were methotrexate (MTX) and cisplatin (CDP), with doxorubicin (DOX) added for some studies.  Patients who did not respond to this combination were treated with high dose ifosfamide.  Surgical methods used included limb salvage (77%), rotationplasty (3.2%) and amputation (19.7%).  None of the 107 patients who did not receive surgery survived. 

Summary survival stats for patients as of March 2008

Candidates

Total Alive

Alive
No Relapse

Alive
1+ Relapse

Alive
with Disease

All Candidates: 1458

754 (51.7%)

613 (42%)

137

4

Protocol: 1032

645 (62.5%)

532 (51.6%)

111

2

Non-Protocol: 426

109 25.6

81

26

2

The total number of candidates with local recurrences was 8.1%.  Survivors of recurrence had all received limb salvage surgery. 

The type of surgery associated with recurrence is broken down as follows:
After demolitive surgery: 3.8%
After rotationplasty: 2.3%
After limb salvage surgery: 9.4%

For those patients that did not survive, the cause of death was:
Disease: 685
Not cancer-related: 5
Treatment-related: 14

Death rates for candidates broken down by timeframe and candidate type:
All Candidates: 1 week–255 months (mean 31.5 mo., median 23 mo.) - 48.3%
Protocol Candidates: 2–255 months (mean 40 mo., median 31 mo.)- 37.5%
Non-Protocol: 1–147 months (mean 21 mo., median 14 mo.) - 74.4%

Follow up imaging of the primary site and the lungs:
First 2 years: Every 2 months
3rd year: Every 3 months
4th year: Every 4 months
5th year: Every 6 months
6+ years: Every year

Survival rates by number of years post-treatment:
Time             All       Protocol         Non-Protocol
5-years         57%       68%             30%
10-years       52%       64%             25%
15-years       51%       61%             24%

In order to better analyze survival data by recruitment year, the records, covering 21 years, were divided into 3 groups of 7 years each:  1982-1998, 1989-1995 and 1996-2002.  Statistically significant findings included:

The authors summarize their findings, saying, "Analysis of data demonstrated that the subgroups that most benefited from the increase were those patients with a worst initial survival: patients candidate to protocols who relapsed and were rescued (survival increased from 27% to 58%), patients metastatic at diagnosis (from 12% to 31%), and patients with tumor in axial sites (from 15% to 42%). Apart from a possible improvement due to a better use of conventional chemotherapy, it seems that these results are due to more aggressive multimodal treatments, including surgery for locations once considered inoperable or the use of iterative lung surgery. It does not seem that second-line chemotherapy influenced survival."

V6N6 ESUN Copyright © 2009 Liddy Shriver Sarcoma Initiative.