The surgical complications of chemotherapy in the cancer patient

THE SURGICAL COMPLICATIONS OF CHEMOTHERAPY IN THE CANCER PATIENT

In the early part of the 20th century operation was the only treatment possibility for most tumors. Even today, in the late l!WOs, operation remains the primary mode of treatment for approximately 70% of all patients with cancer. In 1946 the field of chemotherapy opened when alkylating agents were found to be useful in patients with Hodgkin’s disease. This discovery was followed by the introduction of scores of other chemotherapeutic agents and the beginning of the use of these agents in combination. The use of operation with chemotherapy as an adjuvant treatment, followed. Chemotherapy, earlier almost always given intravenously WV) or orally, is naw given via a number of different routes, including the intraperitoneal, intrathecal, and intra-arterial routes. Today, cancer treatment requires an understanding of what each discipline-surgery, radiation therapy, immunotherapy, and chemotherapy-has to offer. The role of the surgeon in cancer treatment has similarly changed from extirpation alone to include diagnosis, staging, providing routes of access for delivery of chemotherapy, and treating the complications of other therapies. Dealing with the emergencies that arise from intensive chemotherapy has become a new field in the last decade because of the increased use of multiple-drug regimens for almost all kinds of advanced neoplasms. Acute surgical emergencies caused by a reaction to chemotherapy include gastrointestinal (GI) tract hemorrhage from tumor necrosis or direct chemotherapy toxicity to the mucosa, bladder hemorrhage from mucosal irritation by chemotherapeutic agents, abscesses secondary to neutropenic states, perforations due to tumor lysis, pancreatic abscesses, typhlitis from neutropenia, cholangitis and biliary sclerosis from intra-arterial chemotherapy, and peritonitis from intraperitoneal treatment. Pulmonary complications are especially hard to diagnose, since most patients with these problems are on an intensive chemotherapy program that makes them susceptible to multiple pulmonary infections and to a direct toxic effect on the lung. Differentiating beCurr

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tween bleomycin-caused fibrosis or Pneumocystis carinii pneumonia, for example, is impossible without resorting to biopsy. In addition to the acute emergencies, local wound complications may arise from extravasation of chemotherapeutic agents and the chemical irritation of venous sites. Problems of wound healing in the face of chemotherapy are becoming more and more common in surgical practice. When should adjuvant chemotherapy be started in the patient who has just had a mastectomy or a segmental resection? How soon can Adriamycin be started in the sarcoma patient with wide excision wound still to heal? Another problem coming to the fore is the occurrence of a second malignancy resulting from the chemotherapy given for the primary malignancy. Finally, the problems of venous access have become a field by themselves. New catheters have been introduced, new ports are being devised, and new complications are being reported as a result of long-term venous access. GASTROINTESTINAL

COMPLICATIONS

The increasing use of multidrug chemotherapy has resulted in a corresponding increase in the number of GI tract complications secondary to such therapy. The myriad GI tract problems produced by the malignancies themselves, such as obstruction, hemorrhage, perforation, and peritonitis, will not be discussed here; rather, we will consider only the surgical GI complications resulting from chemotherapy. For example, obstruction of the small bowel, a major problem in cancer of the ovary, small intestine, and other intra-abdominal malignancies, is usually not directly caused by treatment. However, the recent introduction of intraperitoneal chemotherapy has led to small bowel obstruction from the intense intraperitoneal fibrous reaction secondary to the chemotherapy, so small bowel obstruction is discussed here as a complication of intraperitoneal therapy. Chemotherapy-caused GI tract hemorrhage and perforation have been widely reported. Infectious abdominal complications of chemotherapy, such as primary peritonitis, are rare and have only been reported in connection with intraperitoneal chemotherapy. Appendicitis and cholecystitis may be complications of chemotherapy and are discussed in that context. Only a few cases of paralytic ileus secondary to chemotherapy have been reported, but the actual clinical incidence may be significantly higher, since the ileus often resolves with nasogastric intubation, does not require operative intervention, and often may not be reported as a complication. Pancreatitis has been reported as a result of the use of specific chemotherapeutic agents. Anorectal complications are well-known se614

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1987

quelae of chemotherapy, especially in patients with leukemia and lymphoma. Finally, there has been an enormous increase in intraarterial chemotherapy, especially intrahepatic, since a totally implantable hepatic pump became available some 5 years ago. The surgical oncologist must be aware of the multiple problems of chemotherapy to make the appropriate treatment decisions for a patient on chemotherapy who presents with a potential complication. Chemotherapy can depress the immune response and mask abdominal symptoms, hampering the diagnosis, especially of abdominal disease. GASTROZNTESTZNAL

BLEEDING

Upper GI tract bleeding is a major complication in patients undergoing chemotherapy (Table 1). Patients on the intensive multidrug regimens commonly given for lymphomas or leukemias are especially prone to GI tract bleeding. The hemorrhage has been considered to be due primarily to tumor necrosis, but recent studies have suggested that injury to the mucosa is the main cause of hemorrhage. Chemotherapeutic agents can cause bleeding both by damaging or irritating the mucosa and by depressing platelet production. Operation is often required for the treatment of such hemorrhage when a conservative medical regimen fails. Besides hemorrhagic gastritis, other types of chemotherapy-induced hemorrhage include peptic or stress ulceration, tumor necrosis, esophagitis, and MalloryWeiss mucosal tears. A large retrospective study of GI tract hemorrhage at Memorial Sloan-Kettering Cancer Center was performed to elucidate the major TABLE

1

Upper

GI Tract

Bleeding

in Patients

With

Malignancy TYPE OF HEMORRHAGE

AUTHORS

INSTITUTION

DISEASE*

NO. OF FTS.

Padmanabhan

Malignancy

55

24

11

10

10

Klein Rosenfelt Hande Fleming

Roswell Park Memorial Stanford NIH Tennessee

49 9 3 4

18

19 0 0 0

6 0 3 4

6 0 0 0

Kemeny

NIH

Malignancy DHGGI DHGGI Gastric lymphoma Burkitt’s

10

1 43 (33%)

Total ‘DHL,

cum

130 dilTuse

6’robl

histiocytic

Surg,

GASTRITIS

ULCER

TUMOR

OTHER

0

0 0

2 32 (25%)

5 28 (22%)

2 18 (14%)

lymphoma.

October

1987

615

causes of massive bleeding in cancer patients. Of the 310 cancer patients who had GI tract hemorrhage, 49 had massive and fatal bleeding episodes. Acute mucosal erosions were the most common cause of hemorrhage, appearing in 16 (32%) of the 49 patients. Thirteen (27% 1 had benign duodenal ulcers and six (12%) had benign gastric ulcers. Only six patients (12%) actually bled from tumors involving the GI tract. Eleven (69% 1 of the 16 patients with mucosal ulcerations were being treated with chemotherapy. Seven were also receiving steroids .” A prospective endoscopic study from the same institution found that gastritis was the most common cause of hemorrhage in patients with upper GI tract bleeding and cancer, occurring in 43% of the patients. The etiology of the gastritis was divided into two areas: agents such as aspirin, Percodan, alcohol, adrenal steroids, indomethacin, and phenylbutazone; and major stress secondary to operation or sepsis. Patients with lymphomas, leukemias, lung cancer, and breast cancer had the highest incidence of GI tract hemorrhage. In 10 of 18 patients with stomach tumors found endoscopically, the tumor was the source of the GI tract hemorrhage.go Another study from Memorial Sloan-Kettering, on the risk factors and mortality in cancer patients with GI tract hemorrhage from stress ulcers, reported a mortality of greater than 50% in patients with hemorrhage from stress ulcers or erosions. For patients being treated with gastric irritants, withdrawal of the medication resulted in improvement in the majority of cases. (Chemotherapeutic agents were not classified as gastric irritants.) Five patients underwent operation for hemorrhage unresponsive to medical management, Near total gastrectomy in three patients provided control of bleeding, while vagotomy and pyloroplasty or ulcer plication in two patients did not control hemorrhage. A near total gastrectomy was considered to be the procedure of choice for ulcers or erosions in the proximal stomach that did not respond to nonoperative treatment.” In a retrospective review of upper GI tract bleeding at Roswell Park, erosive gastritis was found in 24 (44%) of 55 patients with malignancies. Seven patients had gastric ulcers and four had duodenal ulcers. Ten patients (18%) were bleeding from the tumor. Factors contributing to hemorrhage in these 55 patients included chemotherapy, cortisone, aspirin, and stress caused by operation or sepsis. Forty-two of the 55 patients were on chemotherapy, and seven were receiving cortisone therapy only. Ten patients were known to be taking aspirin for pain relief. Of the seven patients with stress ulcers, six had episodes of bleeding during the postoperative period. Nine patients had severe thrombocytopenia due to chemotherapy or sepsis.lo6 In a study from Stanford, 48 patients had GI tract involvement by diffuse histiocytic lymphoma. All received chemotherapy as part of 616

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their treatment. Six patients with stage I disease underwent resection of the lymphoma, and none had GI tract hemorrhage during subsequent chemotherapy. GI tract hemorrhage complicated nonoperative treatment in two of the 16 stage II patients. Three of five stage III patients and four of 21 stage IV patients had GI hemorrhage during treatment. The etiology of the GI hemorrhage was not given. In all, nine (19%) of the 48 patients had some GI hemorrhage during treatment .123 A report from the National Cancer Institute (NC11 on diffuse histiocytic lymphomas involving the GI tract is more specific about the etiology of bleeding. Of 18 patients treated with combination chemotherapy, five underwent complete resection of a tumor involving the GI tract. None of these patients experienced bleeding during chemotherapy. Three (23%) of the remaining 13 patients developed massive upper GI hemorrhage from necrotic tumor, and two of the three died. GI bleeding thus prevented the completion of chemotherapy in approximately one quarter of those patients and contributed to the overall poorer response rates of patients with diffuse histiocyctic lymphoma involving the GI tract.57 Patients with gastric lymphoma were more likely to experience gastric bleeding when treated with chemotherapy if no resection had been performed. In a study from the University of Tennessee, four of five patients with gastric lymphoma receiving Cytoxan, Adriamycin, vincristine, and prednisone who had not undergone resection developed upper GI hemorrhage, for which three patients required operation.45 Primary gastric lymphomas account for more than half of all GI tract lymphomas.17 In general, patients with gastric lymphomas are older than patients with lymphomas at other sites. Recent studies have indicated a trend toward more aggressive treatment of GI tract lymphomas, especially with multiple-drug regimens.45 Most experts agree that lesions more advanced than stage II should be treated with both operation and chemotherapy. The role of operation is not so much curative as to prevent bleeding or perforation during intensive chemotherapy.17’ 16’ When patients with unresected gastric lymphomas experience GI tract hemorrhage during chemotherapy, the probability is greater than 50% that the bleeding is from the lymphoma.gO These patients should undergo gastroscopy to confirm the bleeding site. If the hemorrhage is indeed from the tumor, the patient should undergo gastric resection. In a study from the National Institutes of Health (NIH), in 92 patients with Burkitt’s lymphoma, all treated with chemotherapy, there were ten major episodes of GI hemorrhage. Half of the patients were bleeding from lymphomatous lesions in the GI tract. One of these patients was treated successfully with an emergency hemigastrectomy after the second massive hemorrhage. Three patients had suCurt-

Probl

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1987

617

perficial ulcerations, and two patients had severe candidiasis causing the hemorrhage. One of the patients with candidiasis also had a Mallory-Weiss type of tear at the esophagogastric junction seen at endoscopy. She died a week later and the mucosal lesion and candidal esophagitis were confirmed at autopsy (see Table 1).74 A recent report from the Montreal General Hospital described two patients on chemotherapy in whom GI tract hemorrhage was secondary to a Mallory-Weiss tear in the cardia. The first was a woman with metastatic breast cancer who was being treated with cyclophosphamide, Adriamycin, 5-fluorouracil (5-FIJI, and dimenhydrinate. She began to vomit 30 minutes after the IV therapy and then began to have hematemesis, found on gastroscopy to be from a longitudinal tear below the gastroesophageal junction. The second patient, under treatment with Adriamycin, cyclophosphamide, and cisplatin for metastatic lung cancer, began to vomit 3 hours after a treatment was completed. When hematemesis started a few hours later, emergency endoscopy demonstrated an esophageal tear. In both cases no operation was necessary.43 Candidal infections of the GI tract were found at autopsy in 11% of patients with lymphomas. The esophagus was most commonly involved. Bleeding was one of the leading symptoms and the main cause of fatal complications due to fungal infection.*36 In an autopsy study of patients with hematologic malignancies treated with cytosine arabinoside, 44% of esophageal ulcers were due to fungi, most commonly Candich142 In our study of patients with Burkitt’s lymphoma, 20% of serious GI tract hemorrhages were caused by candidal esophagitis and gastritis.74 When candidiasis is suspected to be the cause of the bleeding, esophagoscopy with esophageal washings is the best diagnostic procedure. Treatment includes oral Nystatin or ketoconazole, or IV amphotericin B for patients who cannot tolerate oral treatment. In summary, GI tract hemorrhage is not an uncommon complication in patients being treated with chemotherapy for malignancies. Superficial erosions rather than tumor are the main causes of bleeding; thus, all patients should be worked up for the etiology of the hemorrhage so that proper treatment can be instituted. The causative mechanism of these erosions is not understood, although the chemotherapeutic agents themselves may predispose the mucosa to damage.137 However, stress, steroids, and anti-inflammatory agents are often involved, in conjunction with the chemotherapy, and it is hard to separate out the exact etiology of the hemorrhages. Treatment is aimed at direct control of the bleeding. In the majority of patients this can be’accomplished nonoperatively. Blood, coagulation factors, platelet transfusions, antacids, and Hz-receptor blockers remain the mainstay of treatment in the 60% of patients who bleed from gastritis or ulceration, On occasion, direct coagula618

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tion by laser or bipolar cautery can control bleeding from isolated ulceration or tumor. When extensive bleeding occurs from tumor, operative resection may be the only recourse. The decision as to extent of, and indications for, operation will depend on the extent of the patient’s disease and the prognosis, as well as the likelihood of successful nonoperative control of hemorrhage. In all cases, appropriate support with platelets and blood factors will be required (Fig 1). PERFORATION

OF THE

BOWEL

Reports of perforation of the GI tract secondary to chemotherapy are surprisingly sparse in the medical oncology literature. Many oncologists anticipated that with the advent of more potent chemotherapeutic regimens, especially for the lymphomas, there would be numerous GI sequelae following treatment of GI lesions because of the mucosal location of the lesions and the rapid response to the chemotherapeutic agents. Actual reports of perforations in such cases have been rare, although in some centers the incidence of primary lymphomas of the GI tract is as high as 30% of all lymphomas (Table 2) .13’ In a study from Memorial Sloan-Kettering Cancer Center, 2.5% of 4,234 patients with non-Hodgkin’s lymphoma had primary GI lesions. No mention was made as to whether perforation was seen when patients were first presented.l”’ A report from Scotland in 1955 reviewed eight cases of bowel perforation secondary to primary lymphomas. None of the patients had been treated prior to perforation. It was concluded that free perforations of primary lymphomas prior to treatment might be more common than the literature suggests.6” Of the 112 patients with primary GI lymphomas seen at Louisiana State, nine (8%) presented with perforating lesions.” The Stanford experience with GI tract lesions from diffuse histiocytic lymphoma was reviewed in 1980. Of 284 patients, 48 had GI lesions at initial evaluation. Most had gastric (56%) or small intestinal (25%) involvement. None of these patients presented with perforation. Treatmentrelated GI tract bleeding or perforation was seen in 12 of the 48 patients. No mention was made of the treatment for these complications.‘23 A study from the NC1 reviewed their experience with patients with primary diffuse histiocytic lymphoma in the GI tract over an ll-year period. All of the 18 patients were treated with chemotherapy. Five of the 18 underwent resection of all intra-abdominal disease. Bowel perforation occurred in one of these five patients before treatment and in one after chemotherapy. In all, six (33%) bowel perforations were seen in the 18 patients, three before chemotherapy and three after.57 Curr

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1987

619

Blockade

Treatment

FIG 1.

of patients

and upper GI tract hemorrhage,

“‘trationtTotal Tumor Resection

Failure 1’

Evaluation

Malignancy

Blood Coagulation Blood Transfusion Platelet Transfusion Factor Transfusion

with malignancy

Suture Ligation of Isolated Ulcer or Tear

Antacids H-2 Receptor 1 Success

Direct Treatment: Laser Coagulation Bipolar Coagulation Sclerosis J

Variceal

With

i LJGl Hemorrhage $ Resuscitate 1

Patient

Gastrectomy

of Prognosis

Success

TABLE

2

Reports

of GI Tract

Perforations

Secondary

to Chemotherapy*

NO. OF AUTHOR,

Y!L4R

Irvine, Contreary, Kosenfelt, Hande, Kemeny, Jones, Antler, Leidich, Meyers, ‘DHL,

CASES

1955

17 112 48 18 92 50 25 r 92

1980 1980 1978 1982 1983 1982 1980 1985

diffuse

histiocytic

DIAGNOSIS

PERFORATIONS

Lymphoma of GI tract Lymphoma of GI tract Lymphoma of Gi tract DHL involving GI tract Burkitt’s lymphoma Acute leukemia Lung carcinoma Lung carcinoma Non-Hodgkin’s lymphoma

lymphoma;

NG, not

8 9

6-12 6 1 7 6 1 6

NO. OF ITS. WITH PEKPORATIONS AFTER CHEMO.

None All All 3 None All NG None 5

given

A recent study from Memorial Sloan-Kettering Cancer Center reviewed 92 previously untreated children with non-Hodgkin’s lymphoma, of whom six had perforation during the course of their induction chemotherapy, two after resection, with breakdown of ileocolic anastomoses. Thus, four (4%) of 92 had perforations as a result of tumor necrosis secondary to chemotherapy. All had stage III or IV lymphomas. The three patients who were treated operatively survived the operation, but two had a fatal relapse. One patient who had mediastinal disease died at home 5 days after receiving daunorubicin. The bowel perforation was seen at autopsy. It was concluded that as treatment for non-Hodgkin’s lymphoma in children became more intensified, the complications of treatment would increase. The investigators stressed the importance of increased awareness of the possibility of bowel perforation in these patients and felt that aggressive surgical intervention was appropriate if perforation was diagnosed.” In our 92 patients with Burkitt’s lymphoma, seen at the NCI, there was one case of bowel perforation before chemotherapy. None of the 69 patients with GI tract lesions had perforation due to the chemotherapeutic regimen.74 A syndrome of bowel necrosis has been described in patients with leukemia being treated with multiple-drug chemotherapy. In a report from Jacksonville, of 50 patients treated for acute leukemia, 14 experienced abdominal catastrophes. Autopsies, performed in seven of the patients, disclosed necrosis of the bowel and peritonitis. Cytosine arabinoside was thought particularly responsible for these complications as a result of a direct toxic effect on the GI mucosa and by blocking DNA synthesis.70 Another article from Washington, DC, described four patients with cecal necrosis and perforation after chemotherapy. Vincristine was Cm-r

Probl

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1987

621

considered the offending agent producing an ileus that predisposed the bowel to perforation by other chemotherapeutic or steroidal agents,77 Most solid tumors do not metastasize as single or multiple lesions to the GI tract, and when there are metastases, perforations are uncommon. There are a handful of reports of the occurrence of small bowel perforations secondary to metastatic lung cancer. In an autopsy study from New York Medical College, of 423 patients with primary lung cancer, 58 (14%) had GI metastases. These included 33 cases with metastases to the esophagus. Thus, 25 patients had intraabdominal metastases, 11 to the small bowel only. Six perforations were reported, all in the small bowel lesions. There was no mention of the use or timing of chemotherapy” Leidich and Rudolf, in a 1981 review of small bowel perforations secondary to primary lung cancer, found only eight cases of small bowel perforations secondary to lung cancer metastases reported in the world literature. Chemotherapy caused the perforation in only one of the eight cases.86 Colonic perforation due to pseudomembranous enterocolitis secondary to chemotherapy has not been reported in the literature. However, at least one textbook mentions the existence of this phenomenon.67 At the City of Hope National Medical Center we have seen two cases in the last year of fatal pseudomembranous enterocolitis associated with chemotherapy administered without antibiotics. The presentation is identical to that of pseudomembranous enterocolitis secondary to antibiotics. Summary

of Bowel

Perforation

Perforation of the small bowel from chemotherapy acting on mural lesions is unusual. The GI lymphomas are the most prone to this complication but even in these circumstances the incidence of perforation is generally reported as less than 20%. Treatment of bowel perforation varies with the site and cause. In general we feel that small bowel perforations should be resected, with reanastomosis of the healthy bowel. Colonic perforations, especially in the debilitated patient, should be treated with resection and diverting colostomy. In patients with cecal necrosis, an ileostomy with transverse colon mucous fistula must be done as a life-saving procedure. There has been some speculation that chemotherapy can produce a syndrome identical to antibiotic-associated pseudomembranous colitis. Although this idea has been presented in textbooks, there are no case reports of this phenomerlon. If a pseudomembranous colitis does occur-and we have certainly seen it in patients on chemotherapy and antibiotics-we favor following the guidelines of Greenberger5” and treating with vancomycin. If abdominal symptoms (pain, ileus) 622

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1987

progress, an ileostomy with colostomy should be performed so that vancomycin can be instilled directly in the colostomy and ileostomy, decreasing the danger of perforation.

PARALYZ'ZC ZLEUS Vincristine sulfate (Oncovin) has been in the chemotherapist’s armamentarium for over 20 years. The two most common side effects of treatment are neurotoxicity and bone marrow depression. Constipation and paralytic ileus have been reported as rare toxic complications. The early work on vincristine toxicities, with vincristine used as a single agent, included a 1962 report from London, in which constipation was reported as a side effect in 10 (53%) of 19 patients. One of the ten patients developed a paralytic ileus 1 week after treatment.” A 1963 Chicago study reported GI atony as a side effect of vincristine therapy in two of 21 patients. The therapy, which included neostigmine, enemas, and cathartics, did not seem to shorten the 6-day course of the problem.56 A study of the usefulness of vincristine alone in patients with lymphoma and leukemias reported findings in 35 patients. Fifty percent had constipation that was relieved with laxatives. Three (8.5%) of the 35 had a paralytic ileus, and one required small bowel decompression for 8 days.14 In 1966 a death from vincristine-related paralytic ileus was reported. The patient had abdominal pain and distension 4 days after receiving vincristine therapy. The abdominal distension increased in the ensuing 2 days. Abdominal radiographs showed marked distension of the whole small bowel and the colon. Nasogastric suction was started, but the patient died in the next 2 days. Marked distension of the entire small bowel and part of the colon was found at autopsy. There was no mechanical obstruction or peritonitis.14’ Neurotoxic effects of vincristine have been associated with a pathologically proved distal demyelination and axonal degeneration.” The paralytic ileus may be due to this cause. However, study of the myenteric plexuses of patients with GI atony did not reveal abnormalities.5” It appears that the complication of paralytic ileus is seen to a significant degree in about 10% of patients receiving vincristine. When a patient experiences abdominal pain and marked colonic distension while on vincristine therapy, the possibility of drug-related paralytic ileus should be kept in mind. Therapy is generally confined to nasogastric or small bowel tube decompression. However, perforation from severe paralytic ileus has been reported. All patients with vincristine-induced ileus should be carefully monitored for the possible need for surgical intervention if distension becomes too massive. This clinical syndrome is probably similar to the pseudoob-

struction syndrome reported in connection with phenothiazine administration. If distension of the colon becomes so marked that the cecum is greater than 14 cm, the risk of perforation is significant. The therapeutic options are laparotomy with cecostomy or colostomy, or decompression of the colon with the colonoscope. The latter has been described in a recent report of 10 patients with Ogilvie’s syndrome. All had successful decompression with the colonoscope, with no recurrence of the condition. The authors advocated the use of colonoscopy for decompression in patients with massively dilated large bowel but no signs of peritonitis, perforation, ischemic colitis, or hemorrhage. They felt that a tap water enema of 1,000 ml could be safely used in preparation, and that liberal air insufflation should be avoided during the procedure. Perforation was avoided by following these guide1ines.l” The only other chemotherapeutic regimen that has been reported to cause paralytic ileus is the combination of amscarine (m-AMSA) and etoposide W-16) in a man with acute myelomonocytic leukemia who developed paralytic ileus 3 days after receiving a 5-day course of m-AMSA and VP-16. The patient, treated with nasogastric suction, died after 2 weeks of septic shock. Postmortem study disclosed dilated bowel but no perforation or peritonitis.” In conclusion, vincristine sulfate and vinca alkaloids are known to produce peripheral neuropathies that can lead to a paralytic ileus. Other new chemotherapeutic agents may also have similar properties. If a patient develops a paralytic ileus after chemotherapy, decompression with nasogastric suction is advised. If most of the dilation is in the large bowel, colonoscopy can be used for decompression, Timely use of these treatments should minimize the need for operative intervention. ANORECTAL

COMPLICATZONS

Anorectal complications are uncommon but well-documented problems in patients with lymphoproliferative disorders and solid tumors being treated with intensive chemotherapy (Table 3). The infections are believed to be associated with the granulocytopenia caused by the chemotherapy, and the treatment often requires surgical drainage. A 2.2% incidence of rectal infection was reported in a study of patients with blood dyscrasias. The rectal infections seen in patients with leukemias tended to be more painful, more severe, slower healing, and more resistant to antibiotics than rectal pmblems seen in the general pppulati0n.l’ In a large autopsy study from Iowa of 705 patients with leukemia or lymphoma, 15 (2%) had anorectal abnormalities, including four perirectal abscesses and 11 anorectal ulcers.“’ The study by Prolla and Kirsner from the University of Chicago found nine (6.1% 1 anorectal complications at autopsy 624

Cur-r Pro&l Surg, October

1987

TABLE 3. Anorectal

Complications NO. OF ITS.

AUTHOR

NO. (o/o) OF ANORECTAL PROBLEMS

DISEASE

Men-ill Earle Pdla

22 188 148

Small cell SmaIl cell Leukemia

lung lung

Schimpff Kemeny Birnbaum Givler

421 92 409 705

Leukemiadymphoma Bud&t’s lymphoma Leukemia LeukemiaAymphoma

7 (32) 15 18) 9 (6.1) 21 3 9 15

(5) (3.3) (2.2) L2.1)

Of 581 patients with malignancy in of 148 patients with leukemia.‘14 a Baltimore study, 21 of 25 rectal complications were in the 421 patients with hematologic malignancy (5%). Furthermore, 20 of these patients were receiving induction chemotherapy, which suggests that these problems usually occur early in the course of treatment when the most intensive chemotherapy is being administered.13’ Two studies from the NC1 of patients with small cell lung cancer reported an increased incidence of perirectal complications in patients with solid tumors receiving chemotherapy. In one, 15 (8%) of 188 patients receiving chemotherapy for small cell lung cancer had anorectal complications. Again, all the anorectal complications occurred during the period of induction chemotherapy.37 In another report on 22 consecutive patients with small cell lung carcinoma, seven patients (32%) developed an inflammatory anorectal lesion during induction. All patients had symptoms of perianal pain, pruritus, or tenesmus before anorectal disease was diagnosed; in some cases the symptoms occurred for more than a week before the lesion could be diagnosed. In six of the seven patients the anorectal disease began within I day of the granulocyte nadir caused by chemotherapy. Three patients had perirectal abscesses, two had anal fissures, and two had thrombosed hemorrhoids. The patients with abscesses required incision, drainage, and IV antibiotics. The other patients were treated with sitz baths, local analgesics, and IV antibiotics.g7 The anorectal lesions seen in patients receiving chemotherapy are perirectal abscesses, anorectal ulcers, occasional fissures (sometimes with infections), and thrombosed hemorrhoids. Treatment varies from center to center and with the severity of the complication. In the NCI study stool softeners, local heat, and IV antibiotics were used as a first approach to treatment. Six of the 15 patients required subsequent incision and drainage of an abscess. Granulocytopenia was considered the major factor involved in development of the infection; however, a history of anal abnormalities such as hemorCur-r

Prod

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1987

625

rhoids, diarrhea, or constipation preceded these infections in most cases .13’ In our own study at the NIH of 92 young patients with Burkitt’s lymphoma (average age, 17 years), all treated with chemotherapy, three (3%) developed perirectal abscesses and all drained spontaneously after treatment with antibiotics and local heat.74 There is some controversy over the possibilities for prevention of these anorectal complications and the treatment. All agree that careful rectal examination prior to treatment is necessary to identify patients at increased risk. Patients with irregular bowel habits before and during treatment should be treated with stool softeners or antidiarrheal medications to correct the irregularities. During treatment in any patient with preexisting anorectal disease, digital rectal examinations, instrumentation, and enemas should be avoided. The hallmark of all of these lesions once they present is rectal pain. Once this symptom is present, close attention to the anorectal area may aid early diagnosis and treatment. The use and timing of operation must be clinically tailored to each individual. IV antibiotics should be used immediately. Local treatment such as warm packs or sitz baths may enable spontaneous drainage, avoiding operation. The enthusiasm for radiation therapy as treatment for perianal lesions seems to have diminished, especially after the randomized study from Baltimore (Table 4) of radiation therapy for perianal lesions in leukemic patients. In that study, adults with acute leukemia, granulocytopenia, and a localized inflammatory skin lesion were randomly assigned to no radiation therapy or to receive 400 rad to the area as a single treatment, with a repeat course in 7 days. All patients were treated with warm compresses, low-bulk diets, stool softeners or antidiarrheal agents, and systemic antibiotics. Operation, performed only if there was fluctuance, consisted of a minimal incision and drainage. There was no significant difference between the two groups with regard to resolution of the infection or the time to resolution.ss If there is a fluctuant perirectal lesion that is not improving with antibiotic therapy, incision and drainage should be

TABLE

4.

Randomized Inflammatory

Study of Radiation Lesions in Adult

RESPONSE TO THERAPY

Complete Partial Progression No. of patients Median days response

626

to complete

Therapy Leukemia NO. (%) IRRADIATED

for

Perianal

NO. (%I NOT IRRAIXATEIJ

5 (711 2 (29) 0 7 11

3 (60) 1 (20) 1 (20) 5 12

Curr

Probl

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October

1987

carried out as the second step in management. The addition of radiation therapy is not beneficial, although the numbers in the random study are too small to make that the firm basis for such a decision. Only those patients with perianal lymphoma can be theoretically expected to benefit. It seems clear that in the absence of severe systemic toxicity, conservative nonoperative treatment is appropriate until the white cell count nadir is reversed. PANCRE4TZC

TOXICITY

Pancreatitis, a rare complication of chemotherapy, has been reported, particularly with L-asparaginase, the most common cause of chemotherapy-induced pancreatitis. t-Asparaginase, used mainly for the treatment of leukemias and lymphomas, acts by inhibiting protein synthesis; thus, organs with the highest rates of protein synthesis, like the liver and pancreas, are most sensitive to the effects of this drug. The incidence of pancreatitis has been reported as high as 15% to 16% in patients being treated with L-asparaginaSe ,59,84.104.163 The condition can occur within a few days of treatment or as late as 10 weeks after L-asparaginase infusion.158 Pancreatitis, not noted clinically, was often found on autopsy in patients who had undergone treatment with L-asparaginase. Occasionally, the pancreatitis will be complicated by pseudocyst formation, as reported by Samuels et al. from M.D. Anderson Hospital. Nineteen children with leukemia who received L-asparaginase alone or in combination were followed up with ultrasound and laboratory tests to study the development of pancreatic abnormalities. Fourteen of the 19 patients had some increase in pancreatic size on sonography, interpreted as early pancreatitis. Two patients who died had autopsy-proved pancreatitis. One of the children developed a pseudocyst with chronic pancreatitis which was verified at operation. The authors advised using sonography to follow the size of the pancreas so as to permit early withdrawal of therapy in the event of a clinically silent pancreatitis.l” Greenstein et al. described a patient who developed acute hemorrhagic pancreatitis and a pseudocyst in the week following L-asparaginase therapy. This patient was successfully managed by a cystogastrostomy with insertion of a sump tube through the stomach into the cyst.55 In a discussion at the Pediatric Surgical Association in 1983, Dr. Thomas Boles of Columbus, Ohio, described two patients with pancreatitis caused by L-asparaginase, in both of whom pseudocysts formed that required surgical drainage .I” Schaller and Schaller reported a case of L-asparaginase-induced hemorrhagic pancreatitis in which a pseudocyst developed, requiring drainage. Eventually, because of continuing septic problems, the patient underwent subtotal pancreatectomy.l” Episodes of Curr

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1987

627

pancreatitis have been reported after combination chemotherapy with vincristine, methotrexate, mitomycin C, 5-FIJ, and cyclophosphamide, and after use of vincristine or methotrexate alone.lw Although pseudocyst formation is a rare complication, operation may be required to drain the pseudocyst. Our feeling is that a pseudocyst should be followed by ultrasonography unless it is causing local problems of pressure, obstruction, bleeding, or infection. If it grows or does not reduce in size after 4 weeks of observation, it should be drained either by percutaneous CT-guided drainage or operatively with internal (preferably) or external drainage. Tumor lysis, caused by massive destruction of tumor cells by chemotherapeutic agents, is especially common in Burkitt’s lymphoma because of the sensitivity of the tumor to certain agents. Of the multiple complications that can develop from the tumor lysis syndrome, acute pancreatitis has been one of the most severe. Two cases of acute pancreatitis induced by tumor lysis were seen in the Burl&t’s patients at the NIH. In one case an B-year-old child with relapse of Burkitt’s lymphoma was being treated with high-dose cyclophosphamide.lU On the day after treatment she had acute abdominal pain and her serum amylase level rose. Therapy with hydration and restriction of oral intake was sufficient. The second patient was also being treated with high-dose cyclophosphamide for a relapse of Burkitt’s lymphoma. This patient experienced abdominal pain 1 week after therapy had been discontinued, but during a tumor lysis syndrome. Again, the serum amylase level was elevated. The patient died of progressive metastatic disease. At autopsy evidence of edema and fibrosis of the pancreas was found, as well as lymphoma. Pancreatic involvement with childhood lymphoma can be as high as 43%. Thus, the development of acute pancreatitis during intensive chemotherapy should not be surprising. The symptoms of abdominal pain often seen in these patients may be the result of unrecognized pancreatitis.lU Pancreatitis associated with continuous hepatic artery infusion of FUDR has not been reported. In our series at the City of Hope National Medical Center, of 85 patients treated with continuous hepatic artery infusion of FUDR via an implantable pump, one patient developed acute pancreatitis, diagnosed from the abdominal pain and elevated serum amylase level, and another patient developed a pancreatic pseudocyst. The first patient’s symptoms were relieved by restriction of oral intake and IV administration of fluids. In the second patient a fluid-filled area near the head of the pancreas was noticed on follow-up CT. Percutaneous aspiration yielded serosanguineous fluid that reaccumulated after complete evacuation. A contrast study done through the side port of the Infusaid pump (Fig 2) demonstrated contrast layering out in this cavity. Additional radiographs showed contrast in the pancreatic ducts (Fig 3). We believe 628

Curr

Probl

SW-~,

October

1987

FIG 2. Computed tomogram showing large cavity near head 0) the pancreas. in a 6%year-old man being treated with continuous hepatic artery infusion of floxuridine via an impjantable pump. Note radiopaque pump catheter on side of cavity. When side port of the pump was injected with Renografin, the scan revealed contrast layering into the large cavity.

that the catheter from the pump may have caused an arterial thrombosis and the heparinized saline subsequently leaked out of the arteriotomy, forming a cavity which then eroded into the pancreas. The cavity was drained operatively and the cyst resolved. In summary, certain chemotherapeutic agents, most notably ~-asparaginase, can cause pancreatitis and pseudocyst. Tumor lysis syndrome and continuous hepatic artery infusion of FUDR have also been implicated in the pathogenesis of pancreatitis. Most csses of pancreatitis can be managed medically and with restriction of oral intake. If a pseudocyst develops, draining is often necessary. Whether drainage is performed percutaneously with CT guidance or operatively depends on the expertise at the individual institution. APPENDICZTIS,

NEUTROPENIC

ENTEROPATHY,

AND

TYPHLITIS

Appendicitis

Appendicitis is the most common acute abdominal surgical condition of childhood (Table 5). Although the exact incidence in norCurr

Probl

Sung,

October

1987

623

FIG 3. Same patient as in Figure filled with Renografin.

2. Radiograph

obtained

after CT scan shows pancreatic

duct

mal children is unknown, the incidence of previous appendectomies in Royal Air Force recruits was reported to be 8.4% at their entrance examination.’ Before the advent of chemotherapy, reported cases of appendicitis in children with leukemia were very rare. In a 1965 study from St. Jude Research Hospital, 6 cases of appendicitis were discovered in 22 consecutive autopsies on children with acute leukemia, an incidence of 27%. All 22 patients were in relapse when they died. Ten had appendiceal abnormalities: six had appendicitis and four had leukemic infiltration. Since four of the six patients with appendicitis had been treated with mercaptopurine (6-MP), the toxicity of this agent was thought to have been a factor in the pathogenesis of the appendicitis. The investigators thought that the combination of immune response depression and mucosal injury could cause the inflammatory condition.” Investigators at the City of Hope National Medical Center reported autopsy findings in 408 patients with leukemia and lymphoma; of these, 69 (17%), all on chemotherapy, had necrosis of the lymphoid tissue in the GI tract, especially involving the appendix or terminal ileum.’ In a study of the acute abdomen in children with leukemia from Memorial Hospital, six (2%) of 286 patients developed appendicitis. Four of these patients underwent appendectomy and all survived the postoperative period. The two patients treated nonoperatively did not sunrive. It was felt that if a child with an acute abdomen did not improve after 24 hours of resuscitation with antibiotics, fluid, electrolytes, and blood products, an exploratory laparotomy was indicated.3g 630

Curr

Prohl

Surg,

October

1987

lixl?ll,y

Children, leukemia Children, leukemia, autopsies Children, leukemia, autopsies Leukemia Leukemia Solid tumor, leukemia and l.ymphoma I,eukemia, autopsy I,eukemia, children Leuhemia and lymphoma, autopsies Burkitt’s lymphoma

Johnson

Wagner

Kjornsson Kasmussen Kuffer

ProHa and Kirsnel Sherman Ammmin

Kemeny

286 22

191

11

228 287 259

1 1 3

318 14x

4

21

5

408

2s

69

1

1

1 1 1

1 1 3

1 1

4

0

0

3

0

1

1

Another group, from Los Angeles, came to the opposite conclusion. Based on their experience of a uniformly fatal outcome in five leukemic children with appendicitis treated operatively, they believed that exploratory operation should generally not be done. They cautioned that if the patient was in relapse, the GI complications were a sign of terminal disease, but for patients in remission, an operation might be beneficial.13’ However, a group from Utah reported the successful treatment of appendicitis by appendectomy in a patient in relapse.lX7 In the NIH study, of 92 patients with Burkitt’s lymphoma, 69 had abdominal disease and 33 of these patients underwent resection of the disease. In 21 of the 33, the appendix was removed because it was involved by tumor. In the remaining 71 patients treated with chemotherapy, one patient developed appendicitis and was successfully treated with an appendectomy.74 As advances in the treatment of leukemias and lymphomas are being made, the indications for surgical exploration of the patient with the possible diagnosis of acute appendicitis broaden, since if patients can be supported through such an acute episode, there are chances for remission with newer chemotherapy regimens.

Curr

Probl

Surg,

October

1987

631

Typhlitis is defined as a necrotizing enterocolitis of the cecum often found in neutropenic leukemic patients being treated with chemotherapeutic agents. One report indicated that 10% of patients with leukemia are found to have typhlitis at autopsy.128 In another autopsy study, from Texas Children’s Hospital, of 191 children with leukemia, 19 (9.9%) had advanced typhlitis. The lesions presented in one of three patterns: (1) necrosis localized to the cecum, (2) extensive necrotic lesions in the cecum as well as other portions of the colon and small intestine, and (3) ulceration in the cecum with sporadic ulcers throughout the intestine. Edematous necrotic tissue in the cecal wall was found, usually infiltrated with organisms, especially Pseudomonas aeruginosa. The possible pathogenesis included localized hemorrhage, ulceration, and invasion by enteric organisms due to the toxic effects of the chemotherapy on the mucosa. No explanation was offered for the prevalence of disease in the cecum.154 The early reports on this syndrome were mainly from autopsy studies. If typhlitis developed it was considered a fatal complication. In a 1973 study from Children’s Hospital of Los Angeles, six cases of typhlitis were reported, of which only one came to operation. Symptoms included watery diarrhea and abdominal cramps. Barium enema examination disclosed mucosal irregularity of the cecum with rigidity and loss of haustral markings. Two patients had advanced typhlitis with Pseudomonas aeruginosa sepsis; they died without undergoing operation. In two patients there was a cecal perforation: one a free perforation into the peritoneal cavity and the other into the sigmoid colon. The patient with the free perforation underwent right hemicolectomy and died of sepsis 2 months postoperatively. The authors cautioned against aggressive surgical treatment for this usually fatal complication.140 A report in 1978 reviewed the case of a 48-year-old woman with acute lymphoblastic leukemia who developed typhlitis during induction chemotherapy, when her granulocyte count went down to zero. A right hemicolectomy and ileocolic anastomosis were done, and the patient recovered and went into complete remission. Early surgical intervention was considered the key to this patient’s survival .I” A recent study on the acute abdomen in the immunologically compromised child reported three cases of typhlitis in 35 children with acute abdomens. All three patients had areas of perforation in the bowel. Two of the patients, who underwent right colon resection and ileostomy, are alive and free of disease 2 years postoperatively. Both had leukemia, but neither had leukemic infiltration in the resected specimens. In the third patient the process had spread be632

Cum

Probl

Surg,

October

1~87

yond the right colon and only a cecostomy was performed. The patient died several days later with a pseudomembranous colitis picture at autopsy and again no leukemic infiltrates. It was felt that if the diagnosis of typhlitis can be made early, operative treatment is essential to the patient’s survival.*Z8 A recent report from the Children’s Hospital in Boston reviewed the cases of 77 patients with acute myelogenous leukemia who were receiving chemotherapy. Twenty-five patients had episodes of abdominal pain, fever, and tenderness during periods of neutropenia. Ten also had watery diarrhea, and nine had GI tract bleeding. Seven had enteric organisms cultured from their blood. Nineteen of the 25 children were in the induction period of chemotherapy and five were in the maintenance therapy phase. All patients in this study who were given the diagnosis of typhlitis and had the above-mentioned clinical picture were treated with broad-spectrum antibiotics and bowel rest. Four patients underwent right hemicolectomy. Of the 21 patients who were medically managed, one died. There were four criteria for operative intervention: (1) persistent GI tract bleeding, (2) perforation, (31 clinical deterioration, and (4) development of abdominal symptoms in the absence of neutropenia. In this report, clinical symptoms were not correlated with the actual presence of typhlitis. Thus, medical management chosen in preference to operation may have been used in patients who never had typhlitis.135 In general, the more recent reports have stressed that the improved survival of leukemic patients makes aggressive surgical management more appropriate than it was in earlier years, when chemotherapy was less successful. We feel that severely neutropenic patients should have the benefit of intense medical management first, but if signs of appendicitis or typhlitis are present, exploration is warranted. Neutropenic Enteropathy In the last few years another syndrome, neutropenic enteropathy, has been described in patients on chemotherapy who are severely neutropenic. This condition is similar to typhlitis but more extensive. Patients have abdominal pain, generalized abdominal tenderness, and usually diarrhea, in the setting of severe neutropenia. A recent report from Boston reviewed the cases of 58 patients who had acute abdominal pain and neutropenia with granulocyte counts of less than 1,000/mm3. Half had localized pain and half had generalized pain. Eighteen of the 29 patients with generalized pain were diagnosed as having neutropenic enteropathy. In 11 the symptoms resolved with antibiotic therapy and restoration of the granulocyte count. Seven died, four with autopsy-documented diffuse enterocolitis of the entire intestinal tract. It was concluded that surgical therCurr

Probl

Surg,

October

3987

633

apy should be reserved for patients with localized pain and tenderness. Those patients with diffuse enterocolitis would not be helped by surgical intervention.135 Another report on neutropenic enterocolitis presented the cases of two neutropenic patients who had abdominal pain, rebound tenderness, and bloody diarrhea 9 to 11 days after induction of intensive chemotherapy for leukemia. Both patients recovered without operation, but with the institution of antibiotics and granulocyte transfusions. The differential diagnosis included pseudomembranous colitis, ischemic colitis, typhlitis, and diffuse neutropenic enteropathy. The authors stressed the prudent use of proctoscopy or colonoscopy to aid in determining the diagnosis, as well as stool assay for Clostridium d@cile.‘45 The accepted pathogenesis of the neutropenic enteropathy is bacterial invasion of the mucosa in the severely neutropenic state, resulting in agranulocytic cellulitis. Candida, Pseudomonas, Clostridium, E. coli, and Klebsiella have been implicated as the most likely offending agents. This syndrome has become more common since the advent of more aggressive multimodal chemotherapy has resulted in longer and more profound periods of neutropenia.48 Most surgical oncologists agree that in the severely neutropenic patient, signs of an acute abdomen must be treated cautiously. In general, emergency operation should be reserved for the patient who has a localized problem, perforation, or a deteriorating situation not responding to vigorous medical management with fluids, antibiotics, and granulocyte transfusion. The specific treatment of pseudomembranous colitis with vancomycin should be initiated as soon as the diagnosis is entertained, and continued if the diagnosis is confirmed by assay. Summary

of Appendicitis,

Neutropenic

Enteropathy,

and

7’yphliti.s

We believe that with the advances in chemotherapy, especially in the treatment of leukemia and lymphoma, patients who have signs of appendicitis should be explored, and appendectomy is indicated for appendicitis. Patients with the diagnosis of localized typhlitis should also be considered for operation and colectomy if the cecum is involved. In general, in the very ill patient, an ostomy is safer than a direct anastomosis, but seems to offer little benefit. Finally, for the severely neutropenic patient with abdominal pain, rebound tenderness, and often bloody diarrhea-a clinical picture of neutropenic enteropathy-we advise medical management with antibiotics and granuloqte transfusions. Operation should be reserved for those patients with perforation, severe hemorrhage, or deterioration under medical management. At operation, a bowel resection, often a total colectomy, may be necessary. Here the role of simple ostomy in these seriously ill patients awaits definition. 634

Curr

Probl

Surg

October

1987

COMPLICATIONS IMPLANTABLE

OF HEPATIC PUMP

ARTERY

INFUSION

WITH

AN

As the use of chemotherapy administered by continuous hepatic artery infusion with the totally implantable pump (Infusaid Corporation, Norwood, Mass.) for the treatment of hepatic metastases increases, the complications of this form of therapy have become more clearly delineated. As of June 1985, more than 11,000 pumps had been implanted in the United States, the great majority to treat hepatic metastases from colorectal cancers with continuous hepatic artery infusion of floxuridine (FLJDR). At the City of Hope National Medical Center, 7.5 patients have received continuous hepatic artery infusion of FUDR via an implantable pump as part of a prospective protocol for the treatment of hepatic metastases. The major complications of infusion in this study are listed in Table 6. All these complications except chemical hepatitis and diarrhea may require surgical intervention7” 73 Sclerosing ChoZangitis.-Fourteen (19%) of the 73 patients treated by continuous hepatic artery infusion of FUDR developed an entity which we termed sclerosing cholangitis. In all patients a serum alkaline phosphatase level elevated to three times normal, with only slightly elevated transaminase levels, was a harbinger of the development of sclerosing cholangitis. Contrast-aided percutaneous transhepatic cholangiography (PTC) or endoscopic retrograde cholangiopancreatography (ERCP) of the biliary tree revealed strictures of intrahepatic or extrahepatic bile ducts, or both. Most commonly the area of the hepatic duct bifurcation was involved in the stricture. For the two patients with stenoses confined to the extrahepatic ducts, intraoperative drainage of the ducts was employed. An intensely fibrotic common duct was encountered in both cases, and a T tube was placed after some dilation of the common duct with Bakes dilators (Figs 4 and 5). Both patients drained well postoperatively. After TABLE

6.

Complications of Continuous Artery Infusion of FTJDR With Implantable Pump (n = 861

Hepatic an

NO. COMPLICATION

Chemical hepatitis Sclemsing cholangitis Gastritis or ulcers Diarrhea Cholecystitis Pump pocket problems Pancreatitis

Cur-r

Probl

Surg,

October

1987

39 17 16 6 6 6 2

(‘%j m-s.

OF

(45) (19.81 (18.61 (6.9) (6.9) (6.9) (2.3)

635

FIG 4. Percutaneous transhepatic cholangiogram (PTC) of a 49-year-old woman who had received three cycles of continuous hepatic artery infusion of floxuridine. She had jaundice and abdominal pain. PTC reveals a stricture starting at the bifurcation of the hepatic ducts and extending into the common duct, with a dilated intrahepatic biliary tree. (From Kehepatic meny MM, Battifora H, Blayney DW, et al: Sclerosing cholangitis after continuous artery infusion of FUDR. Ann Surg 1985; 202:176-l 81. Used by permission.)

a period of at least 6 months, the T tube was removed and the stenoses did not reform. No further intra-arterial therapy was given.73 Most patients in the study had both intrahepatic and extrahepatic stenoses (Fig 6). Thus, operative drainage was not considered. As our awareness of this problem increased, continuous hepatic artery infusion was stopped earlier and in many patients this complication resolved without operation or percutaneous drainage. Once sclerosing cholangitis was diagnosed, no further intraarterial chemotherapy was given. Other investigators have reported a significant incidence of biliary stenosis, from 7% to 20%. The clinical picture was identical to that seen at the City of Hope National Medical Center. All investigators advocate immediate cessation of therapy once biliary sclerosis has been diagnosed.15’61’75 The pathophysiology of sclerosing cholangitis is not known. In the autopsy studies at the City of Hope National Medical Center, there were obvious intrahepatic histologic signs of biliary obstruction, such as bile duct proliferation and periportal fibrosis. The extrahe636

Curr

Probl

Surg,

October

1987

FIG 5. T-tube cholangiogram (same patient as in Fig 4) after common duct exploration and placement of a tong T tube. (From Kemeny MM, Battifora H, Blayney DW, et al: Sclerosing cholangitis after continuous hepatic artery infusion of FUDR. Ann Surg 1985; 202:176181. Used by permission.)

patic ducts had lost their epithelial lining, and a dense fibrotic reaction was seen in the duct wall. We have seen several areas of bile extravasation from the lumen of larger ducts. One explanation for this process might be destruction of the epithelial lining layer by the chemotherapy, which would allow bile to extravasate through the basement membrane. The extravasated bile would then cause the intense fibrotic reaction (Fig 7). A publication from Memorial Hospital reported that all the patients who developed the cholangitis had responded to chemotherapy. The data from the City of Hope National Medical Center also agree with this. In fact, at City of Hope the majority of patients with biliary stenosis were complete responders to the chemotherapy infusion.15’13 Curr

Probl

Surg,

October

It)87

637

FIG 6. PTC of a 43-year-old man who had received floxuridine by continuous hepatic artery infusion for 5 months. He had pain in the liver and an elevated bilirubin level. PTC revealed narrowing of the intrahepatic and extrahepatic biliary system, especially severe at the bifurcation of the hepatic ducts.

Cholecystiti.s.-Six of the first 19 patients treated with continuous hepatic artery infusion in the City of Hope study developed cholecystitis and required cholecystectomy. At operation we frequently found a shrunken, fibrotic gallbladder with signs of cholecystitis and fibrosis. Because of the high incidence of cholecystitis in patients receiving chemotherapy by continuous hepatic artery infusion, we now perform a routine cholecystectomy at the time the pump is implanted. The exact etiology of this complication is unknown, but the infusion of FUDR in the cystic artery could have been a factor since the pump catheter tip was located in the gastroduodenal artery proximal to the take-off of the cystic artery. It is also possible that the toxic effects of the arterial infusion of chemotherapy were compounded by the presence of FUDR excreted in the bile.73 Others have also seen a significant incidence of cholecystitis, and all advocate cholecystectomy at the time of pump implantation.“l’ 75

Curr Probl Surg,

October

1987

FIG 7. Postmortem biopsy specimen of hepatic ducts. Note extreme fibrosis surrounding each duct and the denuded endothelial lining of the ducts. (From Kemeny MM, Battifora tl Blayney DW, et at: Sclerosing cholangitis after continuous hepatic artery infusion of FUDR. Ann Surg 1985; 202: 176-l 81, Used by permission.)

G1 Ukeration and Bleeding.-Seven of the 73 patients at the City of Hope had hemorrhagic gastritis or duodenitis from continuous hepatic artery infusion therapy. Although several had severe hemorrhage, surgical intervention was not necessary. Medical management with gastric lavage, antacids, and Hz-receptor blockers was used in all cases. Five patients had duodenal ulcers seen on endoscopy. One had a gastric ulcer. In one patient with a duodenal ulcer, the pump catheter could be seen at the bottom of the ulcer crater on endoscopy. This patient required an antrectomy and a Bilroth II gastroenterostomy with removal of the pump. Ulcers in the other patients resolved after treatment with cimetidine, sucralfate, antacids, and temporaly cessation of intra-arterial therapy. The mechanism of the complication is not known, but we believe there may be perfusion of FUDR though small collateral connections between the hepatic artery and the gastric and duodenal vascular supply. When the pump is implanted, the hepatic artery dissection must be carried distally and proximally from the gastroduodenal artery, to divide as many collaterals as possible. Aside from the direct perfusion, there Cut-r

Probl

Surg,

October

1987

639

is also FUDR secreted into the bile. The bile mixed with chemotherapeutic agent may predispose the duodenal and gastric mucosa to ulceration. Prophylactic use of cimetidine or antacids has not helped prevent these complications. Cessation of the FUDR infusion is necessary for healing. Once the lesions have resolved, arterial infusion of FUDR can be resumed. Memorial Hospital reported a higher incidence of gastritis with continuous hepatic artery infusion. The treatment was the same as in other centers.75 Pump Pocket Problems.--To implant the Infusaid pump, a pocket is made above the fascia in the left upper quadrant of the abdomen. We use the surgical incision (either midline or subcostall to start the pocket formation and then dissect laterally. We close the pocket with interrupted absorbable sutures. Occasionally, seromas have formed postoperatively in the pockets. Needle aspiration and drainage have sufficed as treatment for this complication. Pump pocket infections were seen in three (1%) of 75 patients well after the postoperative period. In all cases fluid aspirated from the pump pocket was positive on bacterial culture. Pseudomonas aeruginosa was the infecting organism in one patient and Staphylococcus aureus was cultured from the aspirate of two others. Continuous irrigation of the pocket with an antibiotic solution was tried in all cases but was not effective. The pump had to be translocated to another area in the abdominal wall and the infected pump pocket was left open and treated with daily dressings. Any erythema in the skin around the pump noticed during regular bimonthly filling should be treated immediately with an oral broad-spectrum antibiotic. If needle aspiration of the pocket yields bacteria, an antibiotic irrigation may be tried. If this is ineffective, after a few days the pump should be removed or relocated. INTRAPERITONEAL

CHEMOTHERAPY

Within the last 10 years, the feasibility and toxicity of intraperitoneal (IPI chemotherapy for carcinomas of various origins with IP spread have been studied. In earlier work the chemotherapeutic agents were infused through a dialysis catheter or a Tenckhoff catheter, but more recently the Porta-cath IP catheter has been utilized.10g The advantage of the IP treatment is that large volumes of fluid with chemotherapeutic agents can be dispersed throughout the peritoneal cavity so that small tumor deposits will be in direct contact with the drugs. As has been demonstrated in animal studies, the chemotherapy agents used can diffuse through the outer layers of the solid tumors.31 The toxic effects of this treatment include per-

640

Cum Probl

Surg, October

1987

itonitis, chemical and bacterial, catheter complications, and metabolic disturbances. In an experimental study on dogs, IP infusion of cisplatin led to IP irritation with bloody ascites, in four of nine animals. One of four animals autopsied S days after the treatment had filmy IP adhesions. In one of three dogs autopsied 22 days after IP treatment a gray-white membrane was found involving most of the peritoneum. No mention was made of the microscopic appearance of these findings.‘” Seventeen patients with a variety of intra-abdominal cancers were treated at the University of San Diego with cisplatin given IP for 4 hours. Three of the 17 patients had abdominal pain, but only one patient developed symptoms of chemical peritonitis. No medical or surgical treatment was necessary.= At the NIH, IP methotrexate was used in patients with intra-abdominal cancer. Three of five patients experienced peritoneal irritation with abdominal pain. In one patient Pseudomonas ae~+nosa peritonitis developed that required cessation of IP chemotherapy and treatment with an IV aminoglycoside.” Another study from San Diego reported on five patients with ovarian carcinoma treated with IP cytosine arabinoside. There were nine episodes of bacterial peritonitis in the five patients. Staphylococcus aureus was cultured in six episodes, Staphylococcus epidermidis in two, and diphtheroids in one. All patients had fever and abdominal tenderness. All were treated successfully with IP and systemic antibiotics. No patients required removal of the catheter.‘” Combination intraperitoneal chemotherapy with cisplatin, cytarabine, and doxorubicin was administered to 31 patients with IP malignancies at San Diego. The single instance of bacterial peritonitis was associated with perforation of the bowel during catheter insertion. In one patient with signs of small bowel obstruction, extensive intraperitoneal adhesions were found at laparotomy.g4 In a study at the City of Hope National Medical Center, four of 40 patients with abdominal carcinomatosis who received intraperitoneal chemotherapy (either cisplatin alone or cisplatin and 5-FW) had peritonitis with abdominal pain, fever, and peritoneal fluid cultures p.ositive for bacteria. The organisms were Pseudomonas in 1 and Staphylococcus epidermidis in three. All patients were treated with IP and IV antibiatics. None required laparotomy for removal of the catheter or drainage. I3acterial peritonitis can be a complication of IP treatment, but operative intervention seems not to be necessary. Since the unique availability of access to. the peritoneum exists in all these cases, IP lavage with antibiotics appears to suffice as treatment. Even though all the signs of peritonitis may be present, in the absence of localized findings the need for an exploratory operation is not indicated. Curr

Probl

SUF~ October19887

641

Other complications in the City of Hope study included cellulitis at the Porta-cath injection site, bowel perforation, and small bowel obstruction. In the one patient in whom local cellulitis developed, the catheter had to be removed. Material cultured Irorn the intraperitoneum and Porta-cath site was positive for Staphylococcus epidermidis. In two patients, contrast studies through the catheters appeared to show the catheter tip in the bowel lumen. In one patient the catheter had gone into both ileum and sigmoid. The catheter was removed and a wedge small bowel resection was necessary. In the other patient laparotomy revealed that the catheter was not into the bowel lumen but only in a walled-off area that looked like bowel on abdominal radiographs. One patient developed small bowel ob6 months after completion of IP chemotherapy. At laparotstruction omy the small bowel was covered with a dense membrane, which has been seen in one other case on relaparotomy after IP treatment. This membrane was causing the adhesions which resulted in the obstruction (Fig 8). It was thought that the membrane probably

FIG 8. Small bowel appearance at laparotomy of a 66-year-old woman with ovarian cancer who was given six cycles of intraperitoneal cisplatin and IV Adriamycin and Cytoxan. Six months after completion of therapy, small bowel obstruction developed. At laparotomy a dense adhesive film was found covering the small bowel and causing the obstruction. There was no carcinoma in the abdomen. (From Braly P, Doroshow, J, Hoff S: Technical aspects of intraperitoneal chemotherapy in abdominal carcinomatosis. Surg Gynecol 1986; 25~319-333. Used by permission.) 642

Cur-r

Probl

Surg,

October

1987

formed as a reaction to the IP chemotherapy, as has been seen in the animal work mentioned earlier.‘” The surgeon must be alerted to the existing problem of peritonitis in patients treated with IP chemotherapy. Most cases will resolve with antibiotic therapy. A recent article on peritonitis in patients on chronic ambulatory dialysis stressed that unless multiple enteric organisms were cultured from the peritoneal fluid, a laparotomy was not necessary. When multiple enteric organisms were found and the patient did not improve on antibiotics (four patients), a laparotomy demonstrated significant pathology, including appendicitis, cholecystitis, perforated diverticulitis and a perforated cecum. None of the 49 patients who had episodes of peritonitis, but not from multiple enteric organisms, required a laparotomy.‘43 The complications of local cellulitis, bowel perforation, or small bowel obstruction have been reported in many of the studies mentioned and usually required surgical management. GENITOURINARY

TRACT

COMPLICATIONS

Chemotherapy can be directly toxic to the genitourinary tract or indirectly toxic by means of the metabolic effects of the chemotherapy-caused tumor breakdown products. CYSTlTIS

Cyclophosphamide is the most widely used chemotherapeutic agent with genitourinary complications. Work in the last 10 years has proved that acrolein, one of the metabolites of cyclophosphamide, is the causative agent in the production of cyclophosphamideassociated cystitis. Acrolein is formed in the bladder by the breakdown of aldophosphamide, the primary metabolite of cyclophosphamide. Acrolein has been found to be the cyclophosphamide metabolite most toxic to the bladder mucosa. Supporting evidence is seen in the ability of agents that bind acrolein, such as N-ace@-L-cysteine (NAC) and 2-mercaptoethane sulphonate, to protect the bladder from developing cystitis .26,27 The actual incidence of cyclophosphamide-induced cystitis is unknown; most papers report from 9% to 25% (Table 7). In our own review of 100 patients with Burkitt’s lymphoma, all treated with cyclophosphamide alone or in combination with other drugs, there were nine reported cases of hemorrhagic cystitis.74 The symptoms of cyclophosphamide-induced cystitis include hematuria, frequency, burning, and urgency. The condition has been reported to develop as early as 24 hours after IV infusion, but can develop as late as many months after the beginning of cyclophosphamide therapy.” 46J*208“‘, 157 Both IV and oral administration Cur-r

Probl

Surg,

October

1987

f343

TABLE Incidence

7. of Cystitis

in Patients

Treated

AUTHORS

NO. OF Pm.

Beyer-Boon Plotz Johnson Reynolds Kemeny

28 54 40 25 100

and

Meadows

With

Cytoxan

NO. (%) OF PTS. DEVELIJPING CYSTITIS

7 7 10 5 9

(25) (13) (2.5) (20) (9)

of cyclophosphamide can cause cystitis. The urine contains red blood cells but no bacteria. At cystoscopy, the mucosa of the bladder is edematous and hyperemic with hemorrhagic areas. The treatment is prompt cessation of cyclophosphamide therapy. After cyclophosphamide is discontinued, the cystitis usually clears in 4 days, but may persist. If the hemorrhage is severe, several treatments have been advocated. Recently, Formalin infusion into the bladder has successfully controlled bleeding. In a report from Philadelphia Formalin was used in six children with cyclophosphamide-induced cystitis. Five stopped bleeding after one treatment with 1% solution and the sixth required a second instillation, of a 4% solution. Hemorrhage did not recur in any of these patients. The report cautioned against the use of Formalin if there is any sign of extravasation on the cystogram, or if there is reflu~.*~’ When Formalin failed in a patient treated at Johns Hopkins, IV vasopressin was used successfully. Within 1 hour of treatment, hematuria had decreased markedly. However, the patient had to be maintained on the vasopressin infusion for over 50 days. The patient died of pulmonary complications not related to the vasopressin.115 If hemorrhage remains uncontrollable, cystotomy with tamponade or cystectomy with ileal loop diversion might be necessary.51’85 Hydration and diuresis have been shown experimentally to help prevent the cyclophosphamide-induced cystitis and should be encouraged as prophylaxis in all patients on cyclophosphamide therapy.“’ NAC and ,&mercaptoethane sulfonate (Mesna) have been successful as protective agents against the cystitis caused by acrolein toxicity. Mesna is almost entirely excreted into the urine, where it bonds acrolein, forming a harmless compound. This agent can be given IV or or~lyLy.38,

89,113

Long-term Cytoxan therapy can lead to chronic fibrosis of the bladder, as shown in an Autopsy study by Johnson and Meadows on 71 children. Forty of the patients had been treated with cyclophosphamide for various malignancies; 31 patients with malignancies who were not treated with cyclophosphamide served as con644

Curr

Probl

Surg,

October

1987

trols. Ten of the 40 patients who had received cyclophosphamide had pathologic signs of fibrosis in the bladder wall, while none of the 31 patients not treated with cyclophosphamide had the same finding. All of the 10 patients with fibrosis had received cyclophosphamide IV, with total doses ranging from 4 to 21 gm. The degree of fibrosis was dose related. Nine of the ten patients had been on therapy for a minimum of 20 weeks, The authors stressed that since bladder wall fibrosis is irreversible, any patients with hemorrhagic cystitis should be monitored carefully when cyclophosphamide is reinstituted, with special emphasis on adequate hydration.6g

CANCER There have been increasingly frequent reports in the literature of bladder cancer as a result of Cytoxan therapy (Table 8). Fairchild et al., reviewing the records of the Armed Forces Central Medical Registry, found 170 cancer patients who had been treated with Cytoxan. Three of these patients had bladder cancer as a new second malignancy, an incidence of 1.8%, which was 9 times greater than the incidence of bladder cancer in the remaining 18,912 patients.40 Cyclophosphamide has also been reported to cause bladder cancer in patients treated for nonmalignant conditions. In 54 patients treated for rheumatoid arthritis or systemic lupus erythematosus, two patients developed bladder cancer 2 and 5 years after cyclophosphamide had been discontinued. In one patient the disease was resected successfully; in the other it proved fatal. This represented a 100-fold increase in the incidence of bladder cancer?’ In a report from The Netherlands on 28 patients who developed hemorrhagic cystitis while being treated with cyclophosphamide, two developed papillary bladder tumors.’ A review of the Portland Veterans Administration Tumor Registry uncovered six patients with transitional cell carcinoma of the renal pelvis or bladder after prolonged courses of oral cyclophosphamide. The authors recommended that all patients with cyclosphosphamide-induced hemorrhagic cystitis should undergo regular cystoscopy and bladder mucosal biopsies to check for

TABLE

8.

Incidence Treated

of Bladder With Cytoxan

AUTHOR

NO. OF PTS.

Beyer-Boon Plot2 Fairchild

Curr

Probl

Surg,

October

Carcinoma

1987

28 54 170

in Patients

BLADDER

NO. OF CARCINOMAS

2 2 3

645

carcinoma. If carcinoma of the bladder develops, treatment should be the same as for a primary bladder malignancy.47 A fibroblastic tumor of the bladder was reported in 1982 as a sequela of cyclophosphamide therapy for Hodgkin’s disease. The patient had been treated 4 years earlier with combination chemotherapy and radiation therapy. He began to have hematuria. Biopsy by cystoscopy was followed by hemicystectomy and pelvic node dissection. The patient was free of disease 3 years after resection.‘l In summary, bladder neoplasms occur with much greater frequency in patients having received cyclophosphamide therapy. All patients who have received cyclophosphamide, especially those who have had cyclophosphamide-induced cystitis, should be followed yearly with urine cytology and cystoscopy when indicated. Even after 10 years, these second malignancies can appear, so these patients should be followed for at least a decade after treatment.155 BLADDER

ATONY

The neurologic toxicity of vim&tine sulfate (Oncovin) has been recognized for more than 20 years. Pathologically, there is demyelinization of peripheral nerves and axonal degeneration. About 4% of patients treated with vincristine experience difficulty in initiating micturition.5z There have been four reported cases of urinary retention and bladder atony. In three cases there was mild to no demonstrable associated neurologic toxicity. These three patients all responded to temporary bladder catheterization; some required additional treatment with urocholine. In our study of Burkitt’s lymphoma patients, there was one documented case of bladder atony in a patient treated with vincristine.74 This complication of vincristine treatment is quite rare, but may serve as a clinical harbinger of further neurologic toxicities. RENAL

TOXICITY

Methotrexate (MTX), cisplatin, mitomycin C, and streptozocin can cause renal failure by direct toxic effects on the kidneys.4s’ 58J112J 151 Cisplatin and MTX can cause necrosis of the tubular epithelium, while streptozocin can cause renal tubular damage leading to Franconi syndrome.46, 4s Acute tumor lysis syndrome has been reported after treatment of leukemias and lyrnphomas.23 The syndrome is caused by rapid lysis of neoplastic cells secondary to chemotherapy. The findings are hyperuricemia, hyperkalemia, and hyperphosphatemia with hypocalcemia. The effects can range from mild renal failure to sudden death. 646

Con-

Probl

Surg,

October

1987

These patients must be well hydrated and have good renal function before chemotherapy is started. Often dialysis must be started prior to giving the chemotherapy if the renal function is borderline. At the NIH, of 100 patients reviewed with Burkitt’s lymphoma, 25 had renal failure sometime during chemotherapy that required hemodialysis in seven patients and peritoneal dialysis in five. There were six sudden deaths, presumed to be from hyperkalemia.74 All patients requiring chemotherapy who are at risk for tumor lysis should have proper venous access established and possibly angioaccess for dialysis, before treatment, to maintain adequate hydration and electrolyte balance. PULMONARY

COMPLICATIONS

Patients who are receiving aggressive antineoplastic therapy are at high risk for pulmonary infection.‘, 54 Such patients present a difficult diagnostic problem. Acute, diEuse pulmonary infiltrates may be due to infection, malignancy, autoimmune disease, and drug or radiation therapy complications. For a successful outcome, the diagnosis must be made rapidly, especially in patients who are already hypoxic.28,63,119 The underlying disease is variable and does not predict the nature of the infiltrate (Table 9). A prospective evaluation of the relative value of aspiration needle, cutting needle, and transbronchoscopic, transbronchial, and open lung biopsy in patients with pulmonary infiltrates has been performed.” Twenty consecutive patients with pulmonary infiltrates in whom the diagnosis had not been made by noninvasive methods were evaluated in a prospective study that examined the use of the four methods of lung biopsy in making the diagnosis. All these biopsies can be performed synchronously. The technique employed was as follows. The patients were placed supine. General endotracheal anesthesia was induced, and the chest was prepared in conventional manner. The cutaneous aspiration biopsy was performed using a 20-gauge 1%inch thin-walled needle inserted into the affected area under chest radiographic guidance; aspiration was performed with a 20-cc syringe. Percutaneous needle biopsy was performed using a Tru-cut biopsy needle (Travenol, Deerfield, Ill.). With an Olympus BF-B3 Bronchofiberscope (Olympus Corp., New Hyde Park, NY) passed through the endotracheal tube and a T adaptor, transbronchoscopic transbronchial forceps biopsy (Olympus FB-1C) can be used for biopsy, The anterior thoracotomy method was similar to that employed by Klassen et al.?’ Open-wedge biopsy of the lung was performed by grasping the apparently affected tissue with a lung clamp, placing a double row of staples with an automatic stapling device Cur-r

Probl

Surg,

October

1987

647

TABLE

9.

Acute Diffuse 39 Patients*

Pulmonary

Infiltrates:

Underlying

Disease

UISEASE Malignancy Acute Acute Chronic Hodgkin’s Other Sarcoma SBzary

in

NO.

lymphocytic myelogenous myelogenous disease lymphoma

6

leukemia leukemia leukemia

3 2 2 7 3 1

syndrome

Total

24

Bone marrow transplant Childhood leukemia Aplastic anemia

5 3

8 (21%)

Total

Immunodeticiency disorder Chronic granulomatous disease Common variable hypogammaglobulinemia Combined immunodeficiency syndrome

2 1 1

Total

Corticosteroid Systemic Other Myelofibrosis

(62%)

4 (10%)

lupus

therapy erythematosus

with

myeloid

2 15%)

metaplasia

‘Modified from Leight GS, Michaelis LL: Open diagnosis of acute, diEuse pulmonary infiltrates pressed patient. Chest 1978; 73:477482.

1(2%)

lung biopsy for the in the immunosup-

across the parenchyma, then amputating the specimen distal to the staples. A chest tube was placed for dependent drainage in all patients. The specimens were then evaluated by histopathologic, microbiologic, and virologic methods. The diagnostic yields of the four biopsy methods were as follows: aspiration needle, 29%; cutting needle, 53% ; transbronchial-transbronchoscopy, 59% ; and open lung biopsy, 94%. Open lung biopsy led to significantly better diagnostic results than the other methods of study. The aspirated tissue can be examined cytologically by staining filtered material by the Papahicolaou method and methenamine silver. Microscopy of tissue specimens is performed after paraffin embedding, sectioning, and staining with hematoxylin-eosin. Gomori’s methenamine silver stain is employed for connective tissue. Biologic 648

Cur-r

Probl

SW-~,

October

1987

assays are performed in tissue culture employing conventional cell lines. In a recent studyB7 all patients were severely ill preoperatively, with 64% having a PO, of less than 60 mm Hg (Table 10). Postoperative morbidity was significant; 21% died of respiratory insufficiency (Table 11). The results of lung biopsies have been reviewed.20’87 The underlying neoplasms were predominantly leukemias and lymphomas. The specific infectious processes were mainly pneumocystitis (24% ) and fungal pneumonia (12% 1.” Other causes such as primary neoplastic infiltrates, bleomycin toxicity, nonspecific pneumonitis, viral and bacterial pneumonia, as well as less common causes, were found (Table 12). In a more recent studyl”’ an attempt was made to identify the etiology of diffuse infiltrates in the immunosuppressed patient by the use of bronchoalveolar lavage. Twenty-six patients were identified, all of whom were immunosuppressed after renal transplantation or treatment for neoplasia. A specific diagnosis was made in 21 (70%) by cytologic examination of the fluid and in 93% by a combination of cytologic and microbiologic studies. The most common diagnosis was, as in other studies, Pneumocystis carinii infection. In addition, opportunistic infections from other organisms were also identified by cytology. Approximately 65% of the patients recovered from the initial episode. The most appealing aspect of bronchoalveolar lavage is the safety and the ability to obtain cellular material from the lung. This effort involves fiberoptic bronchoscopy with vigorous washing of the middle lobe or lingula in patients with diffuse infiltrates, and selected bronchi in other areas. Twenty-milliliter aliquots of sterile saline are instilled and aspirated to obtain the sample. Gram smears are prepared from the centrifuged lavage material. Various other stains can be added as indicated. TABLE 10. Laboratory

Findings*

PARAMETER

NO. (%) OF PTS.

Hypoxemia: PO, 80 mm Hg PO, 60 mm Hg Leukopenia (WBC 4,000/mmsI Anemia (Hb 10 gm) Thrombocytopenia (platelets Coagulation defects

38 27 19 17 14 9

*Modified

from

the diagnosis munosuppressed

Cum

Probl

Surg,

October

1987

1OO,OOO/mm’~

Leight GS, Michaelis LL: Open lung of acute, diffuse pulmonary infiltrates patient. chest 1~8; 73:477-%~.

(91) (64) (451 (411 (33) (21)

biopsy for in the im-

649

TABLE

11.

Clinical

Features

in the

Postoperative

Period* NO. (WI or

COMPLICATIONS

Pneumothorax Wound dehiscence Hemoptysis Postoperative None l-3 days >3 days

ITS.

3 (71 1 (2) 1 G!l

ventilatoly

assistance 24 157) 4 (9.5) 14 (33)

Outcome Recovery Died (respiratory Died (nonpulmonary

29 (69) 9 (211 4 (9.51

insufficiency) cause)

‘Modified from Leight GS Jr, Michaelis LL: Open lung biopsy for the diagnosis of acute, diffuse pulmonary infiltrates in the immunosuppressed patient. Chest 1978; 73~477-482.

An alternative approach, using empirical treatment of patients with local and diffuse pulmonary abnormalities, has been reported.156 This retrospective study suggests that empirical treatment without an invasive diagnostic procedure results in an overall 50% mortality. Of greater concern, however, is that all eight patients with TABLE Pathologic

12. and

Microbiologic

Diagnoses* NO.

(70)

10

(24) (121 (71 (71 (7) (5)

Specific diagnosis Pneumocystis pneumonitis Fungal pneumonia Leukemic infiltrate Bleomycin pneumonitis Viral pneumonia Gram-negative pneumonia Pulmonary fibrosis Pulmonary infarction Necrotizing vasculitis Atypical mycobacteria Total

30

71

Nonspecific

12

29

pneumonitis

5 3 3 3 2 1

(2)

1

(21 121

1 1

I21

*Modified from Leight GS Jr, Michaelis LL: Open lung biopsy for the diagnosis of acute, diffuse pulmonary infiltrates in the immunosuppressed patient. Chest 1978; 73:477482.

Cur-r

Probl

Surg,

October

1987

diffuse pulmonary abnormalities died after the empirical treatment. The authors suggested it is possible in the localized infiltrate to attempt empirical treatment since there will be time for an invasive procedure if the patients do not respond to the empirical treatment. However, for those with diffuse infiltrates it is imperative to move rapidly to an early diagnostic method to allow specific treatment if survival is to be expected. Diagnostic thoracoscopy has been advocated. In this procedure41 seven patients have been described in whom the cause of pulmonary infiltrates without pleural effusion was diagnosed by creation of an artificial pneumothorax and by diagnostic thoracoscopy. The arguments made support the safety of the approach. However, virtually all of the patients had localized lesions within the lung parenchyma and none had diffuse infiltrates, as immunocompromised patients do. This technique, therefore, requires much more evaluation before it can be used in immunosuppressed patients. It appears, therefore, that vigorous efforts should be made to establish the diagnosis of any infiltrate in the immunosuppressed patient or any patient with malignancy undergoing immunosuppressive treatment. In the case of localized lesions, bronchoalveolar lavage appears to be an efficacious method and one associated with the least morbidity. However, failure to establish a specific diagnosis warrants aggressive progression to more invasive methods. VENOUS

ACCESS

It is often difficult and frustrating to achieve long-term venous access in the oncologic patient. The use of sclerosing antineoplastic drugs often results in a paucity of peripheral venous access sites. Increasingly, large vessel sites are required for monitoring, for access for chemotherapy, or for delivering total parenteral nutrition. AVAILABLE

ACCESS

ALTERNATlVES

The available alternatives are listed in Table 13. The most common and widely used device for establishing access is the infraclavicular percutaneous subclavian catheter. These catheters can been left in place long periods of time, and their use is extremely well established. Because of concern over the incidence of venous thrombosis with use of polyvinyl chloride catheters, silicone-catheters have been developed, but at present they are difficult to place through a single percutaneous puncture. Increasingly, the silicone-type catheter that requires a surgical procedure for placement (the Broviac or Hickman catheter) is being utilized. Recently the Hickman or Broviac-type Curr

Probl

Surg,

October

1987

651

TABLE Long-term

13. Venous

Access

in Cancer

Patients

Alternatives Percutaneous subclavian venous catheter Percutaneous internal jugular vein catheter Percutaneous antecubital central vein catheter Saphenous vein to inferior vena cava catheter Surgically placed Silastic cuffed catheters Percutaneously placed Silastic cuffed catheters Available catheters Percutaneous polyvinyl chloride catheters (Intracath, Becton Dickson, No. 3162, Sandy, UT 840701 Percutaneous silicone antecubital central line (Kntrasil Vicra, Travenol Laboratories, Dallas, TX 75220) Silicone cuffed catheters (Hickman or Bmviac, Evermed, Medina, WA 98039) Percutaneous peripheral to central vein silicone catheter (Centrasil-Vicra, Travenol Laboratories, Dallas, TX 7.5220)

catheter has been placed using a percutaneous approach, employing a stylette-catheter placement system similar to that used for placing pacemaker wires .78 This attractive alternative is receiving increasing emphasis .ls3 Silastic right atrial or superior vena caval catheters are the preferred type. At present the double-lumen (2.2- or 4.5 mm) catheter is our preferred material. An overall complication rate of 19% has been recorded with the Silastic catheter.116 Arteriovenous polytetrafluoroethylene grafts have been employed in cancer patients when no other access is available. These grafts are preferentially placed in the upper arm by an end-to-side brachial artery to axillary vein technique. Approximately 30% of the grafts become occluded with time, although some have remained patent for 4 years.l16 The infection rate of 3% (9 of 103) was remarkably low. COMPLICATlONS

OF LONG-TERM

VENOUS

ACCESS

The primary complication is venous thrombosis. Conventionally, one accepts a central venous thrombosis rate from an indwelling central line of approximately 5% .lol However, this is the clinically identified occlusion rate; the real thrombosis rate is probably much higher. In an autopsy study, Ryan et al. identified a 25% prevalence rate of central venous thrombosis after the use of indwelling central lines.‘” This is probably much nearer the true incidence, as in a prospective study using elective contrast-enhanced venograms, we examined 22 catheters at the time of placement and then at lo-day intervals. In two patients (10%) clinical evidence of thrombosis developed, although it was not major, and an additional five patients 652

Curr

Probl

Surg,

October

1987

had radiographic evidence of complete (three) or partial venous occlusion. Thus, 33% had at least radiographic evidence of partial or complete occlusion of a major central vein.l’ The presumption has been that occlusion is due to the catheter composition, although many of the patients are receiving parenteral nutrition via the catheter and the high osmolality of the delivered solutions has not been excluded as causative. Certainly, in animal studies,16” silicone was less likely to cause thrombosis in the venous system than were the polyvinyl chloride catheters. In a randomized study comparing the Silastic Hickman Broviac catheter with the conventional percutaneous polyvinylchloride catheter, 50 patients were studied.ls3 All patients underwent venography at the time of catheter removal. No significant differences were seen in the complication rates associated with use of the two catheters. Fibrin sheath formation was greater in the Hickman Silastic group, an unexpected finding. The use of heparin in the infusion mixture has been recommended and is widely employed, but there are few evaluable studies. Heparin in continuous low-dose infusion has been evaluated in a retrospective study in patients receiving total parenteral nutrition.“’ At a heparin dosage of less than 6,000 units/day, 5.4% of 129 patients developed central venous thrombosis. The diagnosis was based on clinical suspicion, followed by radiologic, Doppler, or autopsy confirmation in the majority. By contrast, at dosages above 6,000 units/day, 1.2% of 858 patients developed a TPN-related thrombosis. The preference for the percutaneous subclavian route over the peripheral to central “long line” route is based on success rate in achieving central position3’ (Table 14) and the freedom from infectious complications (Table 15). The number of mechanical complications has been greater with the percutaneous subclavian approach (Table 16). Consequently, it seems wise to pursue the use of silicone catheters where applicable. Following the experience of physicians involved in bone marrow transplantation, the early placement of sil-

TABLE

14.

Central

Venous

CATHETER

Peripheral Subclavian

Catheterization*

LINE

to central

N0.t

791 310

SUCCESS RATE

77% 95%

UURATION, DAYS (MFAN)

32 (l-297) 34 11-300)

*From Daly JM, Lawson M, Speir A: Intravenous access in chemotherapy patients. Int Adv Surg Clncol 1981; 4:59-K. Used by permission. i-Total of 1,101 placed in 1 year’s experience. Cur-r

Probl

Surg,

October

1987

653

TABLE

15.

Infectious Catheter‘s*

Complications

With

COMPLICATION

Ckntral

SUBCL4VL4N

PERlPHEXAL

5 2 0 1

39 3 2

Fever Positive blood culture Infusion site infected Pain IV line contaminated Phlebitis Thrombosis Edema ‘From

Daly

JM,

Lawson

chemotherapy patients. Used by permission.

M, Speir

Int

Venous

Adv

3

1 52 7

1

2

A: Intravenous Surg

Oncol

access 1981;

in

4:59-82.

icone catheters appears to be justified in patients about to embark on long-term aggressive antineoplastic therapy. The difficult problem of evaluating the patient with a fever who has a central venous catheter has been sufficiently addressed. If patients have no other sites of venous access, we currently maintain the catheter, with the use of antibiotics given through the catheter if necessary, rather than immediately withdrawing the line with the problem of replacement in the absence of good access sites and in the presence of profound leukopenia and thrombocytopenia. The other alternative-changing the catheter across a guide wire-has considerable appeal, but is not applicable to the tough Silastic catheters. Our experience with 94 catheter exchanges has been documented were removed in an effort to exclude the (Table 17) .g3 The majority catheter as a possible cause of fever. The average time from the first exchange to the removal of the catheter was 18.6 days, which gave TABLE Reason

16. for

Removal

of Central

RRASON

Therapy completed Patient died Infectious complications Mechanical complications Other Total ‘From Daly JM, Lawson chemotherapy patients. Used by permission. 654

Venous

Catheters’

SUBCLAVMN

PERIPHERAL

63 75 12 (5%) 49

226 160 106 (20% J 20

24

22

223

534

Speir A: Intravenous access in mt Adv Surs Oncol 1981; 4:59-82.

M,

Curr

Probl

Surg,

October

1987

TABLE Central

17. Venous

Catheter

REASONS FOR FXCH.4NGE

Exchange END OF ‘I’KEATMEN3

Fever (not catheter related) Initiation Mechanical problems Reposition Leaking Total ‘From Maher during total

Over

a Guide

Wire* SIJSPECTED

‘I‘HHOMBCISIS

AC:C:IDENTAL REMOVAL

DEATH

SEPSiS

TOTAL

3

4

14

17

55

4

0 1

1 1

7 2

1 3

17 11

3 1 33

0 0 4

1 1 8

2 0 25

1 2 24

7 4 94

17

8

MM, Henderson DK, Brennan MF: Central venous catheter exchange in cancer panmterak nutrition. Nat/ Intraven Ther Assoc 1982; .5:54-60. Used by permission.

patients

an additional catheter life of 1,305 days. Only 3 of the 94 catheters subsequently met the criteria for catheter-related sepsis. The impact of this approach on the number of catheters removed for suspected sepsis is documented in Table 18, by a retrospective comparison with the experience prior to the instigation of the catheter exchange. LOCAL COMPLICATIONS INFILTRATIONS

OF

CHEMOTHERAPY

Extravasation of antineoplastic drugs accounts for 2% to 5% of all complications from these drugs.64 At least 14 drugs have the potential for causing local morbidity when extravasation occurs7’64: cytarabine, actinomycin D, BCNU, bleomycin, chromomycin A3, daunomycin, doxorubicin, DTIC, mechlorethamine, mithramycin, mitomycin C, streptozocin, vinblastine, and vincristine. Extravasation of these drugs causes a progressive local ulceration and tissue neTABLE

18,

Effect

of Catheter

Exchange

on

Catheter

Removal

for

Suspected

1975-1977

Catheters Catheters Catheter Catheters of sepsis *From

used for removed exchanges removed

Maher

MM,

TPN, total for suspected for fever as suspected

IIendersun total

cancer patients during 60. Used by permission. Curr

Probl

Surg,

October

1987

sepsis source

Sepsis* 1978-1981

NO.

(%I

NO.

1%)

105 38 0 S/38

(100)

252 35 55 11135

(100)

(36) (0) (21)

DK, Bowman MF: Central venous parenteral nutrilion. Nafl In~aven

(141 (22) (311

catheter exchange in TIwr Assoc 1982; 5:54-

655

crosis. The ulcers generally do not heal spontaneously and can produce functional impairment if they are over tendons or joints. Several studies of the histology of ulcers produced by subcutaneous infiltration of chemotherapeutic agents have shown vasodilation and stasis at 24 hours after infiltration, endothelial vacuolization by 72 hours, and ulceration of the epidermis and absence of vessels at 5 days. There have been no signs of inflammatory changes .s2,‘OS,132 Other studies in rats had reported similar findings, stressing again the lack of an inflammatory response. A study in rats by Rudolph et al., using intradermal injection of Adriamycin at a fixed concentration but in various volumes, showed a dose-response relationship between the volume of Adriamycin injection and the size of the resulting skin ulceration.125 The time required for healing was also dose related. When 0.1 ml of Adriamycin (2 mg/ml) was given, the maximum lesion size was 6 mm and 6 weeks were required for healing. When 1 ml of Adriamycin (2 mg/ml) was given, the maximum lesion size was 25 mm and wounds took 10 weeks to heal. Other studies have also demonstrated a relationship between volume of injection and lesion size.12’ A study by Petro et al. of methods to ameliorate the skin lesions in rabbits compared DMSO, triamcinolone, sodium bicarbonate, and magnesium sulfate. All were given by injection into the site of extravasation immediately after the Adriamycin infiltration. None of the drugs prevented the subsequent skin ulceration.108 Another study, in mice, compared the use of hydrocortisone, dexamethasone, lidoCaine, bupivacaine, phentolamine, and hyaluronidase for preventing ulceration. Again, the drugs were given intralesionally immediately after the Adriamycin extravasation, and again, none of the drugs produced any benefit.“’ The management of these chemotherapy extravasation wounds varies in different centers. The location of extravasation on the body is an important variable influencing the aggressiveness of the remedy. If the lesion is over a tendon or a joint space, severe functional losses may result from contractions and therapy must be instituted early. The dorsum of the hand is a particularly bad site of extravasation and the 14 drugs mentioned earlier should probably not be infused at this site. When extravasation does occur, the infusion should be stopped immediately. Blood should be withdrawn through the needle to ensure that as much of the drug as possible is removed. Some authors advise aspirating the bleb with a needle on a syringe. Most authors advise injection of hydrocortisone through the infiltrated needle or catheter. There is no expeiimental evidence that this maneuver is useful, but the reports from the NCI suggest tht it reduces the local discomfort. Some authors then advise ice packs; others advise warm packs. Those that advise cold feel this will reduce the swelling.‘18 666

Cut-r

Probl

Surg,

October

1987

Those that advocate heat feel that the vasodilation will increase drug absorption and decrease the local concentration of the chemotherapeutic agent. There is no experimental evidence to support either treatment. Nothing further is done until the inflammation and edema have subsided. If there is no evidence of healing, the entire area should be excised, including the ulcer and a rim of normal skin. The defect is closed as feasible-primarily, with a split-thickness skin graft, with a myocutaneous flap-or left open to granulate. If the extravasation is over a joint or tendon, the physical therapist should institute range of motion exercises and devise special splints if necessary. Special attention must be paid to extravasations on the dorsum of the hand, commonly used for chemotherapy infusion. If a lesion on the dorsum of the hand is large (>2 cm) and the tendons are exposed, the lesion must be repaired with a myocutaneous flap (Fig 91. A split-thickness skin graft attaches to the tendons, preventing tendon glide and often severely restricting hand motion. This complication must be promptly recognized to limit the amount of extravasation. Surgical consultation should be obtained immediately, although surgical intervention may not be necessary at all or may be performed as a delayed procedure. The primary effort should be directed toward prevention. This requires serious structured education of physicians and medical personnel involved in direct infusion of these agents. When tenuous venous access is all that is available, the placement of large-bore central venous catheters is often safer than infusion. SKIN

INFECTIONS

AND

SEPTIC

THROMBOPHLEBITIS

Chemotherapy-induced myelosuppression lowers a patient’s ability to resist skin infections by bacteria, fungi, or viruses. Most disseminated cutaneous infections are seen in patients with white blood cell counts of less than 500/mm3. The infections come from widespread blood-borne organisms. Pseudomonas, KIebsielZa, and Serratia are the most common bacterial agents, Aspergillus, Candida, and Mucor the common fungal agents, and herpes simplex and varicella-zoster the most usual viral agents.l’ Skin lesions are. present in 30% of patients with Pseudomonas bacteremia.l’ The Pseudomonas skin lesions include (1) vesicular clusters; (2) ecthpa gangrenosum, a round, painless lesion with a necrotic center and erythematous rim; (3) cellulitis, with a necrotic center; and (4) red macules, located mainly on the torso. The cellulitis associated with Pseudomonas infection may have fluctuant subcutaneous nodules that should be treated with incision and drainage. Some of these infections may be deep, with pus dissecting into the muscle. This type of extensive infection also requires surgical drainage.13’ I59 Curr

Pt-obl

Surg,

October

1987

657

656

Curr

Probl

Surg,

October

1987

When a neutropenic patient develops Pseudomonas sepsis and ecthyma gangrenosum, antibiotics are the first line of therapy. However, if the lesions progress and are necrotic, excision is thought by many to be the best therapy.35 Local staphylococcal skin infections are also seen in patients receiving chemotherapy. These are evident as furuncles, intensive inflammatory skin reactions leading to necrosis of the central area. Many of these lesions must be incised and drained while the patient is covered with antibiotic treatment.35 Suppurative thrombophlebitis, a severe complication of prolonged IV therapy, can be fatal in the immunocompromised cancer patient on chemotherapy.105 A 1970 study reviewed the case of 521 burn patients treated with IV therapy. Twenty-four patients (4.6% 1 developed suppurative thrombophlebitis. For the 11 cases diagnosed clinically, fever was the most common sign. A purulent exudate from the lumen of the vein was the next most common sign. Erythema, edema, and local pain were not usually seen. Hebsiella was the most common organism, and gram-negative organisms in general were much more frequent than gram-positive organisms. Once the diagnosis of suppurative thrombophlebitis was made, surgical excision of the offending vein was performed. Almost 50% of the cases were diagnosed only at autopsy. The authors stressed the importance of early diagnosis and quick surgical intervention to prevent a fatal outcome. They thought the only certain treatment was to excise the entire length of involved vein and allow the surgical wound to heal by granulation.146 A more recent article about suppurative thrombophlebitis in childhood stated that thrombophlebitis in children is almost always related to IV therapy. It also stressed the importance of surgical treatment of the suppurative form of phlebitis.13’ In a series of 92 patients at the NIH with Burkitt’s lymphoma, all of whom received IV chemotherapy, there were two cases of septic thrombophlebitis; both patients required excision of the affected veins.74 Thus, septic thrombophlebitis can be seen in 2% to 4% of patients on IV treatment. It can be a fatal complication in the neutropenic patient if it is not recognized and treated early. If purulent material can be expressed from a venipuncture site, the vein should be surgically exposed and the section involved in the suppurative reaction resected. CHEMORADIOTHEHAF’Y

AND

WOUND

Of great concern to clinicians managing multimodality chemotherapy is the impact such patients require elective or emergency The indications for surgical intervention CUFF Probl

Surg,

October

1987

HEALING

patients with aggressive on wound healing when operations. in the patient already re669

ceiving aggressive chemotherapy are extensive. In many current protocols operation is an elective procedure, either following preoperative adjuvant chemotherapy or as a therapeutic alternative for patients being actively treated. In addition, surgical procedures are often required for staging, debulking, resection of metastatic disease, or for emergencies that arise. Considerable work has been performed, both experimentally and clinically, to examine the effect of antineoplastic agents on wound healing. The majority of wound healing studies have been performed in animals. Interpretation of such studies is limited by the type of wound being studied, type of closure (primary or secondary), and the method of examining wound healing. The effects elicited by various chemotherapeutic agents may differ, depending on whether tensile strength or rate of collagen synthesis is determined, whether rate of development of the inflammatory response or epithelial migration is investigated. Most studies have examined tensile wound strength by measuring wound breaking strength in response to various mechanical stresses that pull the wound apart. Collagen synthesis is commonly examined by recording the incorporation of labeled proline into hydroxyproline, based on the fact that hydroxyproline is almost exclusively present in collagen and that proline is hydroxylated after its incorporation into the peptide chain. Small amounts of collagen are present in elastin, complement, and acetylcholinesterase, but these quantities are small. The measurement of labeled hydroxyproline in the wound is a direct measurement of newly synthesized collagen. Studies of wound healing are complicated by the species of animal used, the time of drug administration relative to creation of the wound, and the dosage schedule employed. Other variations relate to the route of administration, and many studies suffer from the lack of appropriate controls. An extensive summary has been prepared13’ of the effect of various chemotherapeutic agents on wound healing in animals. This summary includes some of our original work on the effects of Adriamycin and radiation therapy in a wounded rat modela32-34, 133,134 Studies on the effect of chemotherapeutic agents in man have been much more limited than those in animals. Several studies have been performed using nitrogen mustard as an adjuvant to examine wound complications. 5-FU, Thiotepa, cyclophosphamide, and Adriamycin have also been studied. From the studies on nitrogen mustardl’, 96,99,100,124 it was suggested that with doses up to 0.4 mg/ kg given in the immediate perioperative period, no significant increase in the rate of wound complications would be found. 5-F’U has been studied in a number of situations.24260,124 The most significant studies were identified in the National Surgical Adjuvant Breast Project. In a phase II study,Z4 one group received .!GFU, 15 mg/kg/day 660

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given IV on postoperative days 7 to 10. This treatment resulted in increased local complications (52%) compared to the placebo group (43% 1. The majority of complications were minor, but there was a 20% frequency of wound infection in the treated population compared to 15% in the control population, with an 8% wound dehiscence rate, compared to 5% in the control group. Although these apparent differences were small, they were considered statistically significant. Similar results were not seen in the colon carcinoma study, perhaps because chemotherapy was administered closer to the time of wounding in the breast cancer study. The dose was the same in both studies, which emphasizes the importance of the interval between time of wounding and administration of drug. This is well illustrated by our own studies on wound healing in animals. Thiotepa has been studied in a number of situations,36’ ” and there is currently no evidence of increased wound complications in patients undergoing adjuvant therapy following breast or colon operation when the dosage is approximately 0.8 mg/kg of thiotepa in the first 3 days after operation. Minor differences in complication rates were found by the Surgical Adjuvant Gastric Cancer Chemotherapy Study Group, ‘l in which treated patients had an overall complication rate of 67%, compared to 46% in the placebo-treated patients. This difference, in a group of 616 patients, was significant. Cyclophosphamide has also been studied as an adjuvant in 621 patients with operable breast carcinoma.1o3 Treatment in these groups was begun within the first 24 hours of operation and involved a 30 mg/kgday IV dose for a 6-day period. The authors of these studies found no adverse effects from chemotherapy on wound healing or on sensitivity to infection, but complete data were not emphasized. In a subsequent study cyclophosphamide was begun 4 days after operation and adverse effects on wound healing were not reported.42 Adriamycin has been used as an adjuvant in the treatment of soft tissue sarcomasl” and no major wound complications were identified, but in this study Adriamycin therapy was initiated after wound healing had been completed. Animal studies suggest that the timing of Adriamycin administration is crucial to the development of impaired wound healing, and that little or no effect is seen if the Adriamycin dose is delayed to more than 7 days after operation, or given more than 7 days before operation (Figs 10 and 11).‘32 When radiation therapy is combined with chemotherapy, greater potentiation of wound healing deficits can be expected. Again, such effects are time dependent. Recently we examined the effects of adjuvant multimodality treatment on wound healing in 105 extremity and superficial soft tissue sarcomas,4 all of which were eligible for en bloc resection with or without perioperative brachytherapy and/or subsequent chemotherCurr

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661

ADR DAY +7

1,800

NOT TREATED

1,600 i2 s 1,400 3 t 1,200

ADR DAY-7 ADR DAY +3 AOR DAY 0

2u) 1,000 E

g 800 ii d 0

600 400

ITROL M +7 DAY -7 VS CONTROL DAY 0 AND DAY +7 = w.vs DAY +3 I P=a.66 7

14 DAYS AFTER WOUNDING

21

FIG 10. Effect of Adriamycin on wound breaking strength at 7, 14, and 21 days. Dosage (gm) needed to disrupt wound plotted against days after wounding of treated and untreated animals. Each data point represents five animals; respective P values are given for each day. (From Devereux DF, Thibault L, Boretos J, et al: The quantitative and qualitative impairment of wound healing by Adriamycin. Cancer 1979: 43:932-939. Used by permission.)

apy. We examined the effects on wound healing in patients receiving adjuvant radiation therapy: wound complications occurred in 22% of patients receiving brachytherapy but in only 3% of those not receiving brachytherapy. Once such a delay in wound healing occurs, the delay to complete resolution and wound healing is markedly prolonged in patients who received adjuvant brachytherapy (Fig 12). In this study only two factors appeared to contribute to the increase in complications seen in the patients receiving brachytherapy: the size and grade of the excised tumor. This was almost certainly due to the fact that patients with large tumors were more likely to receive brachytherapy and patients with high-grade tumors often required more extensive resection. The combination of the large wound with the significant potential for delay in wound healing is compounded by the addition of brachytherapy. In these studies Adriamycin was used, but almost always it was begun 15 days after the operation. As a consequence, the contribution of Adriamy662

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m CONTROL /7J CONTROL STARVED ADRIAMYCIN TREADED 0 DAY 0

1

500

14

21 DAYS POST WOUNDING

L

FIG 11. Wound breaking strength: Comparison of Adriamycin-treated (day 0), starved control, and nonstarved control rats. P < 0.05 at 14 and 21 days, starved vs. treated animals; P = NS, starved vs. nonstarved controls. Starved animals were fed to pair weight of Adriamycintreated animals. (From Deveteux DF, Thibault L, Boretos J, et al: The quantitative and qualitative impairment of wound healing by Adriamycin. Cancer 1979: 43:932-938. Used by permission.)

tin in compounding any delay in wound healing was minimal, as predicted by animal studies.132 The direct effect of adjuvant therapy on other than skin wound healing has been only minimally examined. Delayed long-term effects on arteries have been reported’l but are rare, perhaps because of the limited life span of many patients receiving such aggressive therapy. It appears that a minimum of 10 years is required before the effects of such vascular damage are manifest. The changes, however, appear to be dose dependent. SECOND

MALIGNANCIES

It has been established experimentally that chemotherapeutic agents can cause as well as cure malignancies in animals. Recently Curr

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663

700

600

0 1

500-

l

0 patients not

yethealed

. 400l% z

l

p=o.o005

7 3000

200-

3--

. i

l

t.

loo-

Non-WIT

BRT

Group L

FIG 12. Duration to complete wound healing in brachyradiotherapy (BRT) and non-BRT patients who sustained wound complications. Difference between means is highly significant by unpaired Student t test. In the BRT group wounds had not healed in 14% of patients by 200 days after operation. (From Arbeit JM, Hilaris B, Brennan MF: Wound complications in the multimodality treatment of extremity and superficial truncal sarcomas. J C/in &co/ 1987; 480488. Used by permission.)

evidence has accumulated that chemotherapy in man can also cause second malignancies. Because most of these second malignancies have latency periods of over 5 years, and because many new chemotherapy agents have been recently introduced, the full understanding of the carcinogenicity of chemotherapy continues to evolve. There are many reports in the literature on the development of second malignancy after chemotherapy or combination radiation therapy-chemotherapy. Most of the second malignancies are acute nonlymphocytic leukemias that do not require surgical management. The second malignancies that require surgical management are the solid tumors and the skin cancers. It must be kept in mind that although the incidence of second malignancy is higher after the use of some chemotherapy agents, there is as yet no proof of their direct responsibility for the carcinogenesis. 664

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A comprehensive review of the carcinogenicity of chemotherapeutic agents was published by Klaus Riche from Germany. Six drugs have been shown to be involved in carcinogenesis in man, with a 5to 15-year lapse between the clinical introduction of the drug and the awareness of the carcinogenic side effects. The drugs were busulfan, chlorambucil, cyclophosphamide, melphalan, and methylCCNU. Also, the MOPP regimen with vincristine, procarbazine, cyclophosphamide, and prednisone has been implicated as a cause of second malignancy.121 Cyclophosphamide was one of the first antineoplastic agents shown to be carcinogenic in man. The connection between cyclophosphamide and bladder cancer has been well established. In a review of the cancer cases in the Armed Forces Central Medical Registry, three cases of bladder cancer were identified in the 170 patients treated with cyclophosphamide for other malignancies. This represented a ninefold increase in the incidence of bladder cancer in the 19,000 other cancer registry patients who did not receive cyclophosphamide.40 Cyclophosphamide has also been reported to cause bladder cancer in patients who were being treated for nonmalignant conditions. In 54 patients treated for rheumatoid arthritis or systemic lupus erythematosus, two patients developed bladder cancer 2 and 5 years after cyclophosphamide had been discontinued. In one patient the disease was resected successfully; in the other it proved fatal. This represented a loo-fold increase in the incidence of bladder cancer.ll’ In a report from The Netherlands on 28 patients who developed hemorrhagic cystitis while being treated with cyclophosphamide, two developed papillary bladder tumors.’ Another publication on the use of cyclophosphamide in rheumatoid arthritis in 400 patients reported a 1.4% malignancy rate, with eight hematologic malignancies and one solid tumor.121 Cyclophosphamide is one of the drugs often used in combination chemotherapy of patients with Hodgkin’s disease. Since the longterm survival rate for patients with Hodgkin’s disease is higher than that for most other patients receiving chemotherapy for malignancies, there is more time for a second malignancy to develop, a conclusion reflected in the number of reports of second malignancies in patients with Hodgkin’s disease. In a study from the NC1 of 473 patients with Hodgkin’s disease treated with chemotherapy and/or radiation therapy, there were 34 second malignancies. Twenty-four solid tumors occurred, including five lung cancers, four squamous cell head and neck cancers, three sarcomas, two colon cancers, and ten solid tumors at other sites. Of the 24 solid tumors, ten occurred in patients treated with radiation only, six occurred in patients treated with chemotherapy only, and eight developed in patients treated with both radiation and chemotherapy. Eighteen of the 24 patients have died, 16 of them having evidence of the second maligCum

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nancy at the time of death. One patient is alive with evidence of a second malignancy, and five are free of disease. The report stated that the incidence of second malignancy in patients treated for Hodgkin’s disease increases with time. Thus, the real incidence of second malignancy in patients with theoretically cured Hodgkin’s disease is not yet known147 The incidence of second malignancy in patients with untreated Hodgkin’s disease is also unknown, so the contribution of Hodgkin’s disease itself to the development of a second malignancy is unclear. A 1977 study from Rochester assessed the risk of new cancers in patients with Hodgkin’s disease and concluded that patients exposed to both radiation and cytotoxic drug therapy were at greater risk for the development of a second malignancy than those treated with either modality alone. Second primaries developed in eight of 65 patients: four cases of leukemia, one adenocarcinoma of the colon, a fibrosarcoma, a skin squamous cell carcinoma, and an anaplastic carcinoma. The observation of increased risk was supported by research by the same group on the effects of procarbazine in mice, which showed significantly enhanced carcinogenic@ when radiation was used concomitantly.6 Another publication from Rochester reported two cases of adenocarcinoma of the stomach in young patients (aged 14 and 24 years) after successful control of Hodgkin’s disease with chemotherapy and radiation therapy. The latency period was 5 years in each case. Both patients received abdominal irradiation and chemotherapy as part of the treatment for Hodgkin’s disease. Because gastric cancer is so rare in patients less than 25 years old, it is thought that the combination therapy contributed to the carcinogenesis.” A large study from Milan of 764 patients with Hodgkin’s disease reported a 7.3% incidence of solid tumor as a second malignancy. Of the 15 patients who developed a solid tumor, seven were treated with radiation therapy alone and eight with radiation therapy and chemotherapy. Four patients had skin cancer, four had lung cancer, and two had melanoma. Cancer of the thyroid, stomach, cervix, and tongue, and abdominal leiomyosarcoma were seen in the remaining five patients. Only certain combinations of chemotherapy led to the development of solid tumors. The regimen had to contain an alkylating agent or procarbazine, or both. The authors cautioned against routinely using these agents coupled with extensive radiation therapy and felt this multimodal therapy should be reserved for patients with an unfavorable prognosis.15o In 1986 they updated their experience, reporting findings in a patient population increased to 1,329, from 764. The incidence of solid tumors was 8.3% when basal cell carcinomas were included and 6.7% when they were excluded. The conclusions in the 1980 report were strengthened and reemphasized, especially 666

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those concerning the dangers of combining alkylating agents and radiation therapy.14’ In the review from Colorado of second neoplasms following radiation therapy and chemotherapy, some possible mechanisms of carcinogenesis were proposed. It was thought that the radiation damage to DNA could be amplified by the ability of chemotherapeutic agents to delay or stop DNA repair. The injured cells could then progress to transformation into oncogenic cells. Other factors may include a decreased effectiveness of the host immune system or activation of oncogenic viruses, as is consistent with the development of malignancy in patients on immunosuppressive agents, especially after transplantation. They felt that the combination of radiation therapy and chemotherapy would increase the risk of second malignancy fivefold over the risk from chemotherapy alone. The second malignancies caused by combined modality treatments included carcinomas of the thyroid, breast, prostate, cervix, skin, colon, larynx, and melanomas and sarcomas. It was concluded that using chemotherapy and radiation therapy as treatment for patients with locally or widespread advanced cancer was warranted; however, the risks of second malignancy with adjuvant chemotherapy must continue to be studied and weighed against the benefits of that form of therapy.lo7 REFERENCES 1. Anderson EE, Cobb OE, Glenn JF: Cyclophosphamide hemorrhagic cystitis. J Uroi 1967; 97:857-858. 2. Ammmin GD, Solomon RD: Necrotizing enteropathy. JAA4A 1961; 182:23-29. 3. Antler AS, Ough Y, Pitchumoni CS, et al: Gastrointestinal metastases from malignant tumors of the lung. Cancer 1982; 49:170-172. 4. Arbeit JM, Hilaris BS, Brennan MF: Wound complications in the multimodality treatment of extremity and superficial truncal sarcomas. Unpublished manuscript. 5. Armstrong D: Infectious complications in cancer patients treated with chemical immunosuppressive agents. Transplant Proc 1973; 5:1245-1248. 6. Arseneau JC, Canellos GP, Johnson R, et al: Risk of new cancers in patients with Hodgkin’s disease. Cancer 1977; 40:1912-1916. 7. Barr RD, Benton SG, Belbeck LW: Soft-tissue necrosis induced by extravasated cancer chemotherapeutic agents. JNCI 1981; 66:1129-1133. 8. Beyer-Boon ME, DeVoogt HJ, Schaberg A: The effects of cyclophosphamide treatment on the epithelium and stroma of the urinary bladder. Eur J Cancer-1978; 14:1029-1035. 9. Bierman HR: Human appendix and neoplasia. Cancer 1968; 21:109-118. 10. Birnbaum W, Ahlquist R: Rectal infections and ulcerations associated with blood dysplasias. Am J Surg 1955; 90:367-371. 11. Blixenkrone-Moller N: Mitomycin chemotherapy given in relation to operation for cancer of the abdominal organs. Acta Chir Stand 1959; 117:189196.

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1983; 51:701-711. 18. Brumback RA, Gerber JE, Hicks DG, et al: Adenocarcinoma of the stomach following irradiation and chemotherapy for lymphoma in young patients. Cancer 1984;54:994-998. 19. Burt ME, Dunnick NR, Krudy AG, et al: Prospective evaluation of subclavian vein thrombosis during total parental nutrition by contrast venography (abstractl. Clin Res 1981; 29:264A. 20. Burt ME, Flye MW, Webber BL, et al: Prospective evaluation of aspiration needle, cutting needle, transbronchial, and open lung biopsy in patients with pulmonary infiltrates. Ann Thorac Surg 1981; 32:146-154. 21. Carney CN, Stevens PS, Fried FA, et al: Fibroblastic tumor of the urinary bladder after cyclophosphamide therapy. Arch Pathol Lab Med 1982;

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wound breaking strength in rats: An evaluation by light and croscopy, induction of collagen maturation and hydroxyproline

electron micontent.

Cancer 1980;45:2934-2939. 35. Dreizen S, Bodey GP, Rodriquez V, et al: Cutaneous complications of cancer chemotherapy. Postgrad bled 1975; 58:150-158. 36. Dwight RW, Higgins GA, Keehn RJ: Factors influencing survival after resection in cancer of the colon and rectum. Am J Surg 1969; 117~512-522. 37. Earle MF, Fossieck BE Jr, Cohen MH, et al: Perirectal infections in patients with small cell lung cancer. JAMA 1981; 24612464-2466. 38. Ehrlich RM, Freedman A, Goldsobel AB, et al: The use of sodium Z-mercaptoethane sulfonate to prevent cyclophosphamide cystitis. J Ural 1984; 131:960-962. 39. Exelby PR, Ghandchi A, Langisan N, et al: Management of the acute abdomen in children with leukemia. Cancer 1975; 35:826-829. 40. Fairchild WV, Spence CR, Solomon HD, et al: The incidence of bladder cancer after cyclophosphamide therapy. J Ural 1978; 122:163-164. 41. Faurschou P: Diagnostic thoracoscopy in pleuro-pulmonary infiltrates without pleural effusion. Endoscopy 1985; 17:21-25. 42. Finney R: Adjuvant chemotherapy in the radical treatment of carcinoma of the breast: A clinical trial. Am J Roentgenol Radium Ther Nucl Med 1971;

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5:193-202.

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58. Hanna WT, Krauss S, Regester RF, et al: Renal disease after mitomycin C therapy. Cancer 1981;48:2583-2588. 59. Haskell CM, Canellos GP, Leventhal BG, et al: L-Asparaginase: Therapeutic and toxic effects in patients with neoplastic disease. N En@ J Med 1969; 281:1028-1034. 60. Higgins GA, Dwight RW, Smith JV, Keehn RJ: Fluorouracil as an adjuvant to surgery in carcinoma of the colon. Arch Surg 1971; 102:339-343. 61. Hohn D, Melnick .I, Stagg R, et al: Biliary sclerosis in patients receiving hepatic arterial infusions of floxuridine. J Clin Oncol 1985; 3(1):98. 62. Howell SB, Pfeifle CL, Wung WE, et al: Intraperitoneal cisplatin with system thiosulfate protection. Ann Intern Med 1982; 97:845-851. 63. Hughes RL, Bogdonoff ML, Faber LP: Lung biopsy in the acutely ill-when and how? Cknical Conference in Pulmonary Disease. Chest 1972; 62:484-490. 64. Ignoffo RJ, Friedman MA: Therapy of local toxicities caused by extravasation of cancer chemotherapeutic drugs. Cancer Treat Rev 1980; 7:17-27. 65. Imperial .I, Bistrian BR, Bothe A, et al: Limitation of central vein thrombosis in total parental nutrition by continuous infusion of low-dose heparin. J Am Co11Nutr 1983; 2:63-73. 66. Irvine WT, Johnstone JM: Lymphosarcoma of the small intestine with special reference to perforating tumors. Br J Surg 1955; 42:611-618. 67. Isselbacher KJ, Adam RD, Martin JB, et al teds): Harrison’s Principles of Internal Medicine, Update II. New York, McGraw-Hill Book Co, 1982; pp 1718. 68. Johnson W, Borella L: Acute appendicitis in childhood leukemia. J Pediatr 1965; 67:595-599. 69. Johnson WW, Meadows DC: Urinary-bladder fibrosis and telangiectasia associated with long-term cyclophosphamide therapy. N Engl J Med 1971; 284:290-294. 70. Jones GT, Abramson N: Gastrointestinal necrosis in acute leukemia: A complication of induction therapy. Cancer Invest 1983; 1(4):315-320. 71. Jones RB, Collins JM, Myers CE, et al: High-volume intraperitoneal chemotherapy with methotrexate in patients with cancer. Cancer Res 1981; 41:5559. 72. Kemeny MM, Battifora H, Blayney DW, et al: Sclerosing cholangitis after continuous hepatic artery infusion of FUDR. Ann Surg 1985; 202:176-181. 73. Kemeny MM, Goldberg DA, Beatty JD, et al: Results of a prospective randomized trial of continuous regional chemotherapy and hepatic resection as treatment of hepatic metastases from colorectal primaries. Cancer 1986; 57:492-498. 74. Kemeny MM, Magrath IT, Brennan M: The role of surgery in the management of American Burkitt’s lymphoma and its treatment. Ann Surg 1982; 196 :82-86. 75. Kemeny NE, Daly J, Oderman P, et al: Hepatic artery pump infusion: Toxicity and results in patients with metastatic colorectal carcinoma. J Clin

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