Metastatic osteosarcoma bowel perforation secondary to chemotherapy-induced tumour necrosis

Abstract

Osteosarcoma is the most common paediatric and adolescent primary bone malignancy and is highly chemosensitive. Gastrointestinal metastases from osteosarcomas are rare. Bowel perforation secondary to chemotherapy is a potential serious complication reported in ovarian, colorectal and haematological malignancies. We report the first documented case of chemotherapy-mediated bowel perforation in an osteosarcoma patient with gastrointestinal metastases. A man in his 20s, with a history of resected osteosarcoma in remission, presented with abdominal pain. A computed tomography (CT) scan demonstrated a large calcified intrabdominal mass (15×13×9 cm) consistent with new peritoneal disease. After one cycle of palliative ifosfamide and etoposide chemotherapy, he developed a large bowel perforation and neutropenic sepsis consequently requiring resection of the perforated mass. Chemotherapy-induced bowel perforation is a rare but serious complication that should be considered in patients with osteosarcoma, and other chemosensitive malignancies, with intra-abdominal metastases. Recommencement of systemic therapies after bowel complications must be assessed cautiously on a case-by-case basis.

Background

Osteosarcoma is the most common paediatric and adolescent primary bone malignancy and is characterised by deposition of osteoid or immature bone cells. It has a bimodal age distribution (adolescence and >65 years) with peak incidence between the age of 13 and 16 years, and a male predominance.^{1 2} Metastatic disease is present in less than 20% of patients at diagnosis,³ and survival outcomes are dictated by prognostic factors including location of metastases, histological response to preoperative chemotherapy and completion of surgical resection of the tumour.^{4 5} Osteosarcoma is highly chemosensitive; an improvement in 5-year survival from less than 20% to around 60% was seen with the introduction of chemotherapy.⁶ Treatment with multidrug chemotherapy and surgical resection can yield a 3-year event-free survival of 60%–70%.⁵ Metastases in osteosarcoma occur predominantly via haematogenous spread with the most common site being lungs, followed by bone and lymph nodes.⁷ Gastrointestinal (GI) metastases of osteosarcoma occur infrequently, with only limited cases reported in the literature.^8–19 Longer patient survival and chemotherapy-induced phenotypic changes to tumour cells are thought to underlie this altered pattern of metastases.^{10 20} Given the sensitivity of osteosarcoma to chemotherapy, GI metastases present potential for life-threatening complications including bowel perforation.

Here, we present a case of osteosarcoma with a large GI metastasis of bowel and mesentery, complicated by necrotic bowel perforation and gram-negative neutropenic sepsis due to suspected tumour lysis in response to chemotherapy. To our knowledge, this is the first reported case of chemotherapy tumour-lysis mediated bowel perforation in a patient with osteosarcoma. The case highlights an unusual and morbid complication that must be considered when treating osteosarcoma, and other chemosensitive malignancies, in patients with GI tract metastases.

Case presentation

The patient was diagnosed with localised osteosarcoma of the right distal femur in his early 20s. He underwent an above knee amputation and received pre-operative and post-operative chemotherapy with doxorubicin, cisplatin and methotrexate. He later developed oligometastatic pulmonary metastases, 16 and 36 months from diagnosis, for which he underwent right upper and lower lobectomies respectively. The patient had been disease free for 4 years, when he presented with right sided abdominal pain and distension. An abdominal ultrasound and CT imaging revealed a 15×13×9 cm right iliac fossa mass, with internal calcification consistent with a metastatic osteosarcoma deposit (figure 1A). A Positron Emission Tomography (PET) scan confirmed an F-fluorodeoxyglucose (FDG) avid 16×13×11 cm calcified mass which appeared to involve bowel, and multiple small right inguinal and femoral nodes. Palliative chemotherapy was commenced with ifosfamide 1800 mg/m²/day and etoposide 100 mg/m²/day, day 1–5, on a 3 weekly cycle. Seven days after his first cycle, he presented to the emergency department with fever to 39°Celsius, abdominal pain and haemodynamic instability with hypotension and tachycardia.

Figure 1.

(A) CT image demonstrating large right iliac fossa osteosarcoma metastasis with internal calcification at time of first presentation with abdominal pain. (B) CT image of advanced disease, 6 months post bowel perforation, demonstrating large liver and peritoneal metastases with internal calcification (arrows).

Investigations

Blood tests revealed neutropenia (white cell count (WCC) 0.7×10⁹/L, neutrophils 0.4×10⁹/L) and a CT abdomen revealed a 20×13×23 cm mass with peripheral enhancement of the wall, central low attenuation interpreted to represent fluid and foci of calcification and gas within the mass. The mass was noted to have increased in size compared with previous imaging, largely through an increased fluid component extending into the pelvis. Histopathology obtained from surgical resection of mass and affected bowel (figure 2) revealed tumour involving the large bowel with involvement of serosa, muscularis propria, submucosa and an area of apparent ulceration. Large areas of necrosis were also noted, suggestive of necrotic tumour with adjacent suppurative inflammation and abscess formation. At a sarcoma multidisciplinary team review, with clinical correlation, the reporting histopathologist concluded necrosis could reflect response to chemotherapy.

Figure 2.

Photograph of metastatic tumour resected from bowel mesentery. The image shows the firm white tumour with areas of necrosis. The white areas correspond to osteoid (predominantly fibrous) in the tumour tissue, as confirmed on microscopy.

Treatment

The patient was admitted to the intensive care unit and treated empirically for febrile neutropenia with gentamicin and piperacillin/tazobactam. Antibiotics were switched to meropenem and metronidazole after blood culture growth of extended spectrum beta lactamase Escherichia coli and Bacteroides fragilis. After 2 weeks of intravenous antibiotic therapy, he underwent diagnostic laparoscopy due to ongoing fevers. Infection of the abdominal mass was assessed to be the source of ongoing sepsis and he subsequently underwent a laparotomy for resection of the metastatic sarcoma mass (figure 2). Perforation of the ascending colon and malignant involvement of the rectum were identified. A right hemicolectomy, small bowel resection and an ultralow Hartmann’s procedure were undertaken. Given the extent of intraperitoneal contamination present due to the GI perforation, it was felt that joining the bowel would create a very high-risk anastomosis, hence a colostomy was fashioned.

He had a prolonged post-operative recovery, which was complicated by anaemia requiring packed red cell transfusions, 20 kg weight loss and significant deconditioning requiring rehabilitation with allied health input from physiotherapy, dietetics and social work. He was discharged 4 weeks after hospital admission.

Outcome and follow-up

The patient underwent restaging imaging with a CT scan 6 weeks post resection (11 weeks after first ifosfamide-etoposide cycle). This revealed interval disease progression with the development of multiple new liver metastases. Chemotherapy was recommenced with dose-reduced ifosfamide and etoposide; however, restaging after a further three cycles, demonstrated progressive disease. He had no further episodes of bowel perforation or GI disturbance. Hepatic metastasectomy was considered but abandoned when diagnostic laparoscopy identified extensive peritoneal disease. He was subsequently treated with cabozantinib with a short period of stable disease before ceasing systemic anticancer treatment due to further disease progression including development of high volume peritoneal and liver metastases (figure 1B). He sadly passed away with bowel obstruction 14 months from presentation with intra-abdominal metastatic disease.

Discussion

Bowel perforation is a rare but serious complication of malignancies, with mortality rates up to 21%, even after source control surgery.²¹ While there are no established predictors of bowel perforation in malignancy, tumour factors, choice and dose of chemotherapeutic drugs and patient comorbidities are thought to increase risk. Several mechanisms for bowel perforation in malignancy have been proposed.

Bowel perforation may result from the disease itself, with aggressive tumour progression of a bowel mass invading the bowel wall and leading to rupture and perforation.^{22 23} Where rupture from tumour expansion itself is the cause of perforation, the size of the tumour is possibly an influencing factor.²² Lymphomas, colorectal, ovarian and renal cell carcinomas are malignancies most likely to be complicated by bowel perforation.²⁴ The location of the tumour within the GI tract, and corresponding wall thickness, have also been proposed as factors that may contribute to perforation risk. Vaidya et al reviewed a series of 92 bowel perforations in intestinal lymphoma. They reported a higher frequency of large bowel perforation (59%) relative to small intestine (22%) and stomach (16%) perforations and hypothesised that a relatively lower frequency of gastric perforations may be explained by greater wall thickness of the stomach than that of the small or large intestine.²⁵ Diffuse peritoneal disease, commonly seen in ovarian cancer, may potentially increase the risk of bowel perforation.^{23 26}

Perforation secondary to chemotherapy may occur. Due to the high turnover of intestinal mucosa the GI tract is especially susceptible to the adverse effects of chemotherapeutic agents.²⁷ Chemotherapeutic agents that are frequently implicated with bowel perforations include bevacizumab and paclitaxel, especially when coadministered with steroids.21 24 28 29 Bevacizumab is a vascular endothelial growth factor inhibitor, and its adverse effects are mediated by antiangiogenic and thrombotic effects leading to bowel ischaemia and necrosis.³⁰ Bevacizumab also alters blood flow to the tumour in a manner that enhances chemotherapeutic delivery/effect promoting tumour regression and necrosis.²⁴ Hapani et al reported that with bevacizumab, risk of bowel perforation is dose dependent in a linear fashion.²⁸ At sites of pre-existing bowel inflammation including diverticulitis or ulceration, dual administration may create a nidus for perforation.^{24 28} The chemotherapy agent paclitaxel, on the other hand, has direct effects on intestinal mucosal cells causing mitotic arrest, cell death and necrotic bowel perforation.^{21 29} Coadministration of either of these agents with steroids appears to increase risk of bowel perforation. This is hypothesised to result from enhancing the known adverse effect on healing of intestinal mucosa through inhibition of reparative inflammation, antibody formation and lysosomal function.^{8 31} Patient comorbidities such as previous diverticulitis, ulcers, bowel surgeries or irradiation and recent endoscopy seem to predispose to bowel perforation, at least in colorectal and ovarian cancers.²⁸

Chemotherapy-induced bowel perforations frequently occur early after chemotherapy initiation. In one case series of patients with GI lymphomas, half of the perforations occurred within a month of the first chemotherapy cycle.²⁵ This is consistent with other studies on GI lymphomas where bowel perforation commonly occurred between 4 days and 5 weeks from chemotherapy initiation.^{32 33} An additional study assessing bevacizumab-mediated bowel perforations in a heterogeneous group of cancers (renal cell carcinoma, pancreatic, colorectal and ovarian cancers) found that complications arose within 7 weeks of the first chemotherapy cycle.³⁴ Our patient showed clinical signs of perforation within 7 days of his first cycle of ifosfamide and etoposide. GI tumour disease per se is not essential for chemotherapy-induced perforation, with cases of perforation in the absence of GI tumour disease, and also at sites in the bowel distant to GI tumour disease when present.²⁴ However, increased likelihood of bowel perforation when GI tumour disease is present, is supported by one study where, on exclusion of ovarian cancer patients with bowel metastases, there were no reported cases of bevacizumab-mediated bowel perforation.³⁵

A further proposed mechanism of bowel perforation is tumour lysis in highly chemo-sensitive tumours. Chemotherapy use, in tumours such as Burkitt’s lymphoma which is highly chemosensitive,³⁶ can cause rapid tumour regression, accompanied by tumour lysis and necrosis, weakening the bowel wall and resulting in perforation. Several cases of chemotherapy-driven tumour lysis causing bowel perforation are reported for intestinal lymphomas.22 25 31 36 37 A case of small bowel perforation has also been reported in small cell carcinoma of the small bowel.³⁸ Both small cell carcinoma and lymphoma, along with osteosarcoma, are known to be highly chemosensitive malignancies. In the case of intestinal lymphomas, multiple studies advocate for elective bowel resection prior to chemotherapy to prevent the development of tumour lysis and subsequent complications.^{25 39 40}

To our knowledge, there is only one other reported case of bowel perforation in a patient with osteosarcoma and there are no reports of chemotherapy-mediated bowel perforation in metastatic osteosarcoma. In the osteosarcoma case, disease was localised to the proximal right tibia, with no known GI metastases, and a pre-existing enteric duplication and concomitant steroid treatment were identified as factors contributing to the perforation.²⁷ In our case, we propose chemotherapy induced tumour lysis and necrosis as the mechanism of bowel perforation with contributory factors of GI tract involvement, high tumour volume and a highly chemosensitive tumour type. The timing, with bowel perforation occurring after one cycle of chemotherapy, and histopathology displaying necrotic tumour at the perforation site with large surrounding areas of necrosis, support chemotherapy-induced perforation.

Evidence and guidance regarding recommencement of systemic therapies after bowel complications is limited. In the case of bevacizumab-related bowel perforation, discontinuation without reintroduction is strongly advised after a bowel perforation.²⁸ In our patient, given his disease appeared to be exquisitely sensitive to ifosfamide and etoposide, chemotherapy was reintroduced with the hope of achieving prolonged disease control. Chemotherapy was reintroduced with dose reduction (80%), greater than 6 weeks post resection to allow healing, and with imaging suggesting minimal residual GI disease thereby reducing the potential for further perforation. In our case, reintroduction of chemotherapy did not result in further GI complications, but this decision should be assessed with caution on a case-by-case basis giving particular attention to the choice of therapeutic agents, timing and dosage, and overall goal of treatment.

Learning points.

• Bowel perforation is a rare but serious and potentially life-threatening complication which must be considered when managing osteosarcoma patients with gastrointestinal disease, given the chemosensitive nature of osteosarcoma.

• Treating physicians should have a low index of suspicion for serious intra-abdominal complications for osteosarcoma patients with known gastrointestinal tumour disease on chemotherapy, presenting with abdominal pain.

• Prompt investigation and intervention in these patients, including broad spectrum intravenous antibiotics and surgical consultation is of critical importance. Morbidity and mortality may be increased with concurrent cytopenia including neutropenic sepsis as was observed with our patient, and bowel perforation in this setting is associated with a high mortality rate.

• When considering treatment with chemotherapy or other oncological systemic therapies in osteosarcoma patients with peritoneal disease:

  • Surgical consultation regarding elective bowel resection prior to initiating chemotherapy should be considered for osteosarcoma patients who have large volume gastrointestinal malignant disease, as has been advocated in multiple studies of intestinal lymphoma, to prevent the development of tumour lysis and subsequent complications.

  • Recommencement of systemic therapies after bowel complications must be assessed with caution on a case-by-case basis giving particular attention to the choice of therapeutic agents, timing and dosage, and overall goal of treatment.

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Consent obtained from next of kin.