Dr. Dorreen - Independent Medical Opinion
| Condition | Adenocarcinoma of the Bowel (Agent Orange) |
|---|---|
| Date of Production | October 11, 2012 |
| Doctor's Name | Dr. Mark S. Dorreen, MD, FRCP(Lond), FRCPC, FACP |
1. Background
The Appellant was employed by the Canadian Army Regular Forces: as a serving member from September 12th 1961 to June 29th 1970 and as a reservist from March 16th 1972 to November 24th 1976. He was honourably discharged on both occasions, in 1971 and 1976, and left the forces with the rank of corporal.
With the exception of 6 months' special duties in Cyprus, the Appellant was stationed at CFB Gagetown, New Brunswick, between September 1961 and June 1968. It is a matter of record that he was involved in active field exercises in June 1966 and June 1967, when tests of aerial spraying of Agent Orange were being conducted in the vicinity. At no time during this period were any significant health issues identified.
2. Subsequent diagnosis of malignant lymphoma and colon carcinoma
In May 2005, the Appellant became aware of a lump in the left groin, initially thought to be a hernia. However, this continued to increase in size and, on June 23rd, he underwent surgical biopsy of the mass, confirming a diagnosis of malignant lymphoma. On further histopathological review, this was classified as a diffuse large B-cell non-Hodgkin's lymphoma (NHL) which had transformed from a low-grade, follicular NHL.
No evidence of more extensive spread was identified on CT scan staging and, thus, this was considered to be a localised (stage I) tumour. The Appellant was seen in consultation by Dr. Richard Van Der Jagt, Hematologist at the Ottawa Hospital, Ontario. Once all the necessary information had been collated, the patient went on to receive 8 cycles of combination chemotherapy with cyclophosphamide (Cytoxan), Adriamycin (hydroxydaunomycin, doxorubicin), vincristine (Oncovin) and prednisone, together with the monoclonal B-cell antibody, rituximab (Rituxan) in a treatment protocol abbreviated as R-CHOP
Treatment was administered between August 2005 and the end of January 2006 and, in February 2006, repeat CT imaging was obtained for the purposes of restaging. This test was reported to show thickening within the cecum and, as well, Dr. Van Der Jagt also commented on the presence of mesenteric lymph nodes, with the largest measuring over 2 cm in size. As a result of these appearances, the Appellant was referred for colonoscopy which was carried out on March 16th. This confirmed the presence of a mass in the cecum which, on histopathology was diagnosed as a moderately differentiated adenocarcinoma.
A laparoscopic right hemicolectomy was performed on the Appellant, by Dr. Boushey at the Ottawa Hospital, on May 17th, 2006. At the time of surgery, 2 firm nodules were identified in the liver but biopsy of one of these did not confirm malignancy. Although the formal histopathological report is not available in the materials submitted for review, there is a comment from Dr. Christine Cripps, Medical Oncologist at the Ottawa Hospital, dated July 12th 2006, stating that the colon carcinoma was staged T4N2, with metastatic involvement of 5/14 pericolic lymph nodes removed.
In light of the likely diagnosis of metastatic disease in the liver, Dr. Cripps recommended combination chemotherapy with 5-fluorouracil (5-FU), folinic acid and oxaliplatin, a regimen usually referred to by the acronym, FOLFOX. Treatment was commenced in August but, a month into treatment, his clinical course was complicated by the development of pulmonary embolism, requiring treatment with the anticoagulant, Fragmin. As well, repeat CT scan had shown evidence of extensive metastatic involvement of the liver which was deemed not to be surgically resectable.
By the end of October 2006, there was evidence that the liver metastases had progressed significantly and chemotherapy was switched to the combination of 5-FU, folinic acid and irinotecan (Camptosar) in the FOLFIRI regimen.
The last chart entry from Dr. Cripps, which is included in the supplied documentation, is dated December 19th 2006, at which time the Appellant appeared to be tolerating ongoing chemotherapy well. However, it is a matter of record that he died on July 9th as a consequence of metastatic colon carcinoma.
3. Entitlement claims/ subsequent appeals to Veterans Review/ Appeal Board
i) Claim for pension entitlement- NHL
A claim was submitted in March 2006 but, in a decision by the Department of Veterans Affairs, dated May 29th 2006, this was declined on the basis that, despite evidence of an association between exposure to Agent Orange and an increased risk of NHL, the evidence of exposure to this chemical, by the Appellant, was considered to be lacking.
An entitlement review was submitted and, with strong supporting input from Dr. Van Der Jagt, the earlier decision was reversed and pension entitlement was granted in February 2007 and made retroactive to March 2006, the time when the claim was originally filed by the Appellant. The decision to reverse the earlier decision was based on: a) evidence the Appellant took part in nearby field exercises on the days in 1966 and 1967 when Agent Orange was being sprayed; b) Dr. Van Der Jagt’s assertion that the condition of proving direct contact with Agent Orange would be impossible to meet; c) knowledge that dioxins contaminating Agent Orange may remain undegraded in the environment for long periods of time and d) the fact that the Veterans Affairs Department in the US had already clearly recommended that those developing malignant lymphoma should be compensated whether or not there had been direct contact with Agent Orange.
ii) Claim for pension entitlement - adenocarcinoma of the colon/large bowel
A claim for additional entitlement in respect of the diagnosis of colon carcinoma was made at the same time as the claim for NHL but was rejected in a Minister's decision dated May 29th 2006, citing a lack of evidence supporting an association between large bowel cancer and exposure to Agent Orange.
The decision not to grant compensation was affirmed in an Entitlement Review hearing decision dated October 17th 2007. An appeal launched by the Appellant's widow in September 2008 was turned down, citing a lack of credible evidence for an association linking the diagnosis of colon carcinoma with Agent Orange. In addition, it was acknowledged that the US Institute of Medicine had established that there was a lack of evidence linking Agent Orange with bowel cancer.
A further entitlement claim was launched by the widow in 2009, on the basis that the diagnosis of colon cancer was a consequence of the pensioned diagnosis of NHL but that was denied in a Minister's decision dated October 7th 2009. An Entitlement Review hearing was held on June 29th 2009 but the earlier ministerial decision was affirmed, in both cases reasoning that the diagnosis of adenocarcinoma of the colon was not a direct consequence of the pensionable diagnosis of NHL.
A new appeal was filed in October 2011 by the Area Advocate on behalf of the Appellant's widow and is the subject of an ongoing formal process. An independent medical opinion has been requested.
4. The association between Agent Orange and adenocarcinoma of the colon
The link between exposure to Agent Orange and cancer has been extensively studied, in returned veterans of the Vietnam War, including military personnel involved in the preparation and aerial spraying of Agent Orange in "Operation Ranch Hand", survivors of major industrial accidents associated with release of significant quantities of dioxins, such as the Seveso incident in Italy in 1976, and workers employed in a wide range of potentially hazardous occupations.
No link to an increased incidence of colorectal cancer has been established or suggested in any study. A review of the carcinogenic risks of Agent Orange, by Frumkin for the American Cancer Society, was published in 2003(1) and updated periodically by the American Cancer Society(2). The US Institute of Medicine (IOM), a division of the Academy of Sciences, has assigned 4 categories of likely association between cancer diagnosis and exposure to Agent Orange:
- Sufficient evidence of association
- Limited/ suggestive evidence of association
- Inadequate/ insufficient evidence of association
- Limited/ suggestive evidence of no association
Cancer diagnoses within 30 years of exposure to Agent Orange, eligible for federal compensation are those falling within categories 1 and 2 and include malignant lymphoma, chronic lymphocytic leukemia and soft tissue sarcoma (category 1) as well as lung and prostate cancers (category 2), amongst others. Gastrointestinal malignancies, including colorectal cancer are grouped in category 4 and are not subject to compensation.
In the materials made available for this Independent Medical Opinion, one publication, reporting an increased risk of small bowel adenocarcinoma in certain occupations, was cited(3). In this multinational European study, there appeared to be a significantly increased risk of small bowel cancer in female farm workers; however, no increased association with herbicide use was established either in this group or in any other occupational category. It is also noteworthy that, while case-controls were drawn from the general population, these also included a cohort of 579 patients with colon (large bowel) cancer since, as discussed by the authors of the publication, "..there is no strong indication of occupational risk factors for this disease."
5. The association between Non-Hodgkin's lymphoma and adenocarcinoma of the colon
Several published studies have demonstrated a link between survivors treated for Hodgkin's and non-Hodgkin's lymphoma (NHL) and an increased risk for the development of subsequent second malignant neoplasms (SMN's). These SMN's include both hematological malignancies, e.g. acute myelogenous leukemia and non-hematological cancers ("solid tumours"). Depending on the published report, the risks are attributed to the disease itself and/ or the treatment, usually cytotoxic chemotherapy.
A statistically significant increased risk of solid tumour SMN amongst surviving patients with NHL has been reported in a number of publications(4,5,6,7,8,9,10). These studies generally involved large numbers of patients identified either from national cancer registries(4,7,8,9) or who had been enrolled on clinical trials(5,6) and one was a meta-analysis of 23 different, published studies(10). One UK study(11) reported a trend toward an association of SMN with aggressive NHL of higher stage but which just failed to reach statistical significance.
In some studies, a small but statistically increased risk of colorectal cancer has been reported(4,10) while in others, a trend, statistically non- significant, was observed(5,6,7,9,12). In one study, based on SEER registry data(9) there was a statistically significant association with a prior diagnosis of chronic lymphocytic leukemia/ small lymphocytic lymphoma but not with diffuse large B-cell lymphoma. In a large study of patients treated on British National Lymphoma Investigation protocols, a statistically significant association with colorectal cancer was seen only in those patients who had been treated with CHOP and, in this group, the standardized incidence ratio indicated a doubling of baseline risk(5). A similar relationship to intensive treatment has not been observed in other studies and, indeed, in the meta-analysis of Pirani et al.(10), the association between colorectal cancer with CHOP-type chemotherapy did not reach statistical significance.
Other factors reportedly associated with a significantly elevated risks for a SMN, have included male sex(4,5,8) and age under 60 years(6,7,10,12) although at least 2 studies have demonstrated no such relationship(4,5). In a study conducted by the European Organisation for Cancer Treatment & Research (EORTC)(6), the overall risk of colorectal cancer following a diagnosis of NHL was nonsignificant. However, among the subset of patients < 45 years old at diagnosis of NHL, 3 later developed colorectal cancer, giving rise to a standardised incidence ratio of 12.5. The 95% confidence intervals were, however, very wide (2.6 - 36.5) and no similar statistic has been quoted in any other study.
In order to exclude patients with NHL and a coincidental/ synchronous diagnosis of SMN, all studies, with the exception of one(7), had clearly specified minimum time limits from diagnosis of NHL as a requisite inclusion criteria for analysis, The minimum time was from 6 months(6,11) and either up to 1 to 2 years(4,9) or from end of treatment(8,12). One UK study specified a shorter period of time of 2 months from time of 1st treatment(5). Where analysed, the median time from diagnosis of NHL to that of SMN, varied from 4.4 to 7.5 years with a range of 1 to over 14 years(4,6,8,12). In most cases, the risk of SMN persisted for at least 2 decades after diagnosis of NHL with a cumulative risk varying between 10.5% at 10 years of followup(8,) to 19-21% at 20 years(4,6).
6. Opinion and conclusions
Colorectal carcinoma is a common cancer and, in Canada, it is estimated there will be 23,300 new cases diagnosed in 2012, making this the 3rd most common malignancy after lung and prostate cancer(13). However, it is a disease which will also be associated with 9,200 deaths and is, thus, the second highest cause of cancer-specific mortality after lung cancer. Factors associated with an increased risk of colorectal cancer have been extensively investigated. In a small minority of cases, there are clear, heritable genetic traits, for example, in familial adenomatous polyposis coli and hereditary non-polyposis coli (Lynch syndromes 1 & 2). There is also a clear association with chronic inflammatory bowel disease, namely ulcerative colitis and Crohn's colitis. Other risk factors such as inactive lifestyle, low-residue diets, excess alcohol intake, etc., have been postulated but, in the majority of instances, no clear risk factor can be identified. However, it is also generally accepted that the majority of colon cancers arise through malignant transformation in a preexisting benign adenomatous polyp. In most such instances, polyps will have been present for up to several years before undergoing malignant change. This is in keeping with the multistep theory of carcinogenesis which, in most instances of colorectal cancer, involves several well described mutations of oncogenes and deletions or mutations of tumour suppressor genes in precancerous cells(14). This is normally a lengthy process and it is this knowledge which has, in recent years, led to the setting up of provincial screening programs for colorectal cancer in Canada.
Evidence for and against the association of colon cancer with Agent Orange and/or NHL is presented and analysed, above. Agent Orange is a defoliant comprising two phenoxy herbicides, dichlorophenoxyacetic acid (2,4-D) and trichlorophenoxyacetic (2,4,5-T). Manufacture of 2,4,5-T was unintentionally contaminated by small amounts of dioxin, of which 2,3,7,8-tetrachlorodibenzo-pdioxin (2,3,7,8-TCDD) is considered the most toxic and potentially carcinogenic. The widespread aerial spraying of this agent by the US armed forces during the SE Asian conflict in the mid to late 1960's meant that many military personnel were exposed to the chemical and, in the ensuing years from the end of hostilities, claims for compensation for a variety of illnesses, including different cancers, were filed with the Veterans' administration in the US. Also well known, spraying tests were conducted at CFB Gagetown, New Brunswick, during the same era and has led to similar claims being filed by ex-military personnel in Canada.
As discussed, a pattern of increased risk for certain cancers, including NHL, has been linked with exposure to Agent Orange and these cases are now the subject of successful claims for pensionable benefits both in the US and in Canada. However, with a followup of 40 years from the end of the Vietnam conflict, no study has ever shown a link with an increased risk of colon or rectal cancer and, thus, these cancers are not subject to compensation. In my opinion, therefore, this would make any such claim in regard of the Appellant, untenable.
In respect of the possible association between the Appellant's preexisting diagnosis of NHL and the subsequent diagnosis of adenocarcinoma of the colon, it will be recalled that the first indication of pathology was based on CT imaging of the abdomen carried out as he was completing chemotherapy for NHL, i.e. within 6 months of starting treatment. The diagnosis was subsequently confirmed on colonoscopy and he went on to surgical resection and subsequent multiagent chemotherapy which, unfortunately, failed to halt the inexorable progress of this malignancy and he died within a year after commencing chemotherapy.
As discussed above, evidence for a significant association between NHL and an increased risk of colorectal cancer is inconsistent from study to study. However, the meta-analysis by Pirani et al.(10) does show a small but statistically significant increased risk. Most studies indicate the risk to be highest in younger, male patients. The relationship between diagnosis and preceding chemotherapy is not well established, with only one study reporting a link to CHOP-type chemotherapy. In the meta-analysis, however, this did not achieve statistical significance. In the case of the Appellant it is entirely plausible that the cytotoxic effects of R-CHOP chemotherapy actually served to suppress clinical manifestation of the colon cancer until after that treatment had been completed.
In order to exclude a chance association of two distinct malignancies, i.e. NHL and SMN, most publications specified minimum time periods between the two diagnoses. Where this was analysed, the minimum time lapse was one year, to diagnosis of SMN. A time period of one or more years would certainly be consistent with the natural history of many solid tumours which tend to evolve relatively slowly, when compared with aggressive lymphomas or acute leukemias. For all these reasons, it would be entirely rational to suggest that the Appellant's colon carcinoma was already evolving at a subclinical level, when the diagnosis of NHL was initially established. Given the relatively long carcinogenic pathway leading to the clinical appearance of colon cancer, it is unlikely, in my opinion, that either the diagnosis of NHL or the chemotherapy received for this, is causally related.
In summary, information and evidence relating to the association of both Agent Orange and malignant lymphoma with adenocarcinoma of the colon have been presented and reviewed. Some of these publications were those which were also discussed by Dr. Van Der Jagt and reference has been made to these where appropriate; all cited publications were in reputable peer-reviewed scientific journals.
Based on all this evidence, it is my opinion and conclusion that there is no causal relationship between Agent Orange and colon carcinoma. With respect to the relationship between the diagnosis of malignant lymphoma and colon carcinoma in the Appellant's case, this, too, should be considered one of chance alone. In other words both the NHL and the colon cancer are, in my opinion, synchronous, unrelated malignancies.
References
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Mark S. Dorreen, MD, FRCP(Lond), FRCPC, FACP Medical Oncologist
Associate Professor of Medicine
Dalhousie University
QE2 Health Sciences Centre, Halifax, Nova Scotia