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DIAGNOSIS IN ONCOLOGY
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“And What Other Medications Are You Taking?”
Patients with cancer face a loss of autonomy as they depend on health care providers to navigate the balance of effectiveness and toxicity of treatments that are often perceived as unusually harsh. Increasingly, these factors—as well as the proliferation of available information—lead patients to pursue complementary and alternative medicine (CAM), although the safety and efficacy of such approaches are rarely studied rigorously. Indeed, patients often hide their use of such modalities for fear of disapproval from their physicians, who might reject the notion of employing such unproven treatments.1,2
We present three patients with advanced hepatocellular carcinoma (HCC), a historically treatment-refractory disease that often occurs in patients with significant comorbidities. By asking the open-ended question, “And what other medications are you taking?” we identified a traditional Chinese medicine (TCM), Ling Zhi (Ganoderma lucidum), that has, at least in our experience, been associated with a few durable remissions.
A 78-year-old Chinese man with cirrhosis resulting from hepatitis B infection had been found by surveillance computed tomography (CT) scan 2 years before to have an early-enhancing liver mass with smaller satellite lesions. Exploratory laparoscopy, biopsy, and radiofrequency ablation were performed. Pathology revealed poorly differentiated HCC. After the procedure, his α-fetoprotein (AFP) level declined from 570.6 to 24.9 μg/L but then increased six-fold over the ensuing 3 months. Repeat imaging revealed a new retroperitoneal lymph node and cervical lymphadenopathy. Cytology from fine-needle aspiration of a cervical lymph node showed metastatic HCC. Because this occurred before US Food and Drug Administration approval of sorafenib for use in HCC in 2008, the patient was treated with doxorubicin as first-line chemotherapy. An initial decline in his AFP correlated with stable disease on follow-up CT scans. However, doxorubicin was discontinued after five cycles because of rising AFP and significant fatigue.
Shortly before doxorubicin was discontinued, the patient elected to start Ling Zhi, obtained through an advertisement in a local Chinese newspaper. Within 6 months, his AFP decreased to 6,827 μg/L from a peak of 13,074 μg/L; 2 months later, it decreased again to 15.2 μg/L. Figure 1A shows the full time course of AFP measurements, with doxorubicin initiated at month 14 and stopped at month 18; Ling Zhi was initiated during month 16 (asterisk). His retroperitoneal lymphadenopathy also decreased on ensuing CT scans (Fig 1B, arrows; month 16, left; month 24, right). Notably, his AFP continued to rise after Ling Zhi was started until doxorubicin was discontinued, suggesting that these two agents may have conflicting actions. His HCC remained quiescent for 2 years, with AFP approximately 20 μg/L and no radiographic evidence of progression. At that point, peritoneal carcinomatosis was noted on an interval scan, despite low AFP. Hospice care was initiated, and the patient died shortly thereafter.
Fig 1.A 69-year-old Chinese man with chronic hepatitis B infection had HCC confirmed by fine-needle aspiration after a CT scan showed a large multifocal contrast-enhancing lesion in the right lobe of the liver with probable portal vein thrombosis. Soon after diagnosis, he began taking Ling Zhi and another TCM product, the herbal preparation Gan Fu Le. He was referred to the University of California at San Francisco (UCSF) for consideration for a clinical trial 3 months after starting these TCM agents. A CT scan to determine protocol eligibility showed a dramatic reduction of the liver mass from 8.9 × 4 cm to 5.6 × 4.5 cm. He has now been observed at UCSF for 10 years, developing only mild renal insufficiency and hypertension. Serial magnetic resonance imaging of the abdomen showed progressive reduction in the size of his tumor over the first several years after diagnosis; the mass has since remained unchanged in size at 4.2 × 1.8 cm. CT of the tumor at time of initial diagnosis and magnetic resonance imaging of the residual lesion are shown in the left and right panels of Figure 1C (arrows); AFP was never significantly elevated. The patient continues to take his TCM and has never received any other cancer-directed therapy.
A 72-year-old woman was referred to the National Cancer Centre Singapore for evaluation of AFP level of 1,899 μg/L. CT showed no cirrhosis but revealed multiple contrast-enhancing liver lesions concerning for malignancy, with the dominant lesion measuring 11.8 × 9.3 × 12.7 cm in the right hepatic lobe (Fig 1D, left). There was no evidence of active hepatitis B or C infection. A single metastatic lesion was later detected in the L3 vertebral body. Given her poor performance status and limited therapeutic options, the patient and her family decided to pursue supportive care, declining biopsy. She sought advice from a TCM practitioner and began taking Ling Zhi and Pian Zhi Huang, a TCM preparation including gardenia, notoginseng, and Ling Zhi. After this, she remained asymptomatic, and her AFP declined to 7.2 μg/L (Fig 1A; Ling Zhi initiated during month 2 [dagger]). Repeat CT of the abdomen performed 12 months after diagnosis showed her dominant lesion had shrunk to 5.4 cm in longest diameter, and her lesions were now all hypovascular (Fig 1D, right). Since that time 9 months ago, she has had a stably low AFP level and no symptoms of disease, continuing her TCM.
The medical literature has many reports of spontaneous remission of HCC, found to occur in 0.406% of patients in a systematic review of the placebo arms of 10 clinical trials, including 1,640 patients.3 A review of many of individually published reports of spontaneous remissions revealed that these were categorized as such because there had been no conventional cancer treatment. However, these patients were often noted to have been taking herbal preparations, particularly TCM,4–6 which was thought to provide symptom palliation for HCC.7
Our case series is intriguing in the context of these reports. HCC is felt to be largely refractory to treatment.8,9 Conventional chemotherapy, in single-agent or multidrug regimens, has not shown a survival benefit for patients with advanced or metastatic disease, for whom median survival is generally shorter than 8 months.10–12 Although the multikinase inhibitor sorafenib prolongs survival in patients with early cirrhosis and preserved liver function,12,13 it infrequently leads to radiographic responses and seems significantly less beneficial to patients with advanced cirrhosis.14,15 Furthermore, phase III trials that demonstrated efficacy of sorafenib for HCC specifically excluded patients with bilirubin greater than 3 mg/dL and Child-Pugh class B or greater liver dysfunction.12,13 These criteria exclude the majority of patients with newly diagnosed HCC.16 Thus, not only are the systemic therapeutic options for HCC limited in efficacy, there remains a sizeable population of patients with HCC who are poor candidates for these therapies because of underlying liver dysfunction.17
CAM has come to play a significant role in clinical oncology. In one study, 80% of patients with cancer at a major academic center admitted to employing CAM, with 60% using vitamins (including mega-dose preparations) and 38% using a variety of herbal supplements.1 This is a startling percentage, particularly because one might expect under-reporting by patients inclined to hide this information from their physicians. A similar proportion of patients in phase I clinical trials use CAM in parallel with study drugs.18 Although the patients presented in our report are Asian, CAM use is by no means restricted to that population. It is also noteworthy that the TCM arsenic trioxide, historically a frequent component of CAM, has been incorporated into the treatment paradigm for acute leukemia.19,20
Although the three patients presented here took a variety of CAM agents, all used Ling Zhi, also known as Reishi, prepared from the edible mushroom Ganoderma lucidum (G. lucidum). G. lucidum has been shown to have anticancer activity in vitro and in mouse models of cancer.21 A number of antineoplastic activities have been described for G. lucidum, including nuclear factor κB and protein kinase C inhibition, immune modulation, and direct cytotoxicity.22–24 An epiphenomenon of reduced AFP production without direct antitumor effect is also possible, noting the history of patient 1. These cases underscore the need for oncologists to be aware of CAM agents such as Ling Zhi, not only because they may be active against HCC, but also because concurrent use of these agents with chemotherapy, as in our first patient, might confound the attribution of results in clinical trials.
There are other case reports and a small case series of G. lucidum use in patients with various cancers.25–27 The next step should be to systematically study G. lucidum in patients with cancer. We are attempting to do just that at UCSF and the National Cancer Centre Singapore, but we have been hampered by an inability to find standardized supplies of Ling Zhi prepared according to current good manufacturing practices. We hope that a study will begin in 2011.
The author(s) indicated no potential conflicts of interest.
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Acknowledgment
This report was prepared with approval from the University of California at San Francisco Committee on Human Research and in accordance with the rules on human research at the National Cancer Centre Singapore. Institutional review board approval was not required because the study was retrospective and noninterventional and required no patient contact.
